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<journal-id journal-id-type="publisher-id">Front. Pharmacol.</journal-id>
<journal-title>Frontiers in Pharmacology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Pharmacol.</abbrev-journal-title>
<issn pub-type="epub">1663-9812</issn>
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<publisher-name>Frontiers Media S.A.</publisher-name>
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<article-id pub-id-type="publisher-id">1445328</article-id>
<article-id pub-id-type="doi">10.3389/fphar.2024.1445328</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Pharmacology</subject>
<subj-group>
<subject>Systematic Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Genetic polymorphisms and platinum-induced hematological toxicity: a systematic review</article-title>
<alt-title alt-title-type="left-running-head">Zheng et al.</alt-title>
<alt-title alt-title-type="right-running-head">
<ext-link ext-link-type="uri" xlink:href="https://doi.org/10.3389/fphar.2024.1445328">10.3389/fphar.2024.1445328</ext-link>
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<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Zheng</surname>
<given-names>Yi</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
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<role content-type="https://credit.niso.org/contributor-roles/supervision/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
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<contrib contrib-type="author">
<name>
<surname>Tang</surname>
<given-names>Mimi</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
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<role content-type="https://credit.niso.org/contributor-roles/Writing - review &#x26; editing/"/>
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<contrib contrib-type="author" corresp="yes" equal-contrib="yes">
<name>
<surname>Deng</surname>
<given-names>Zheng</given-names>
</name>
<xref ref-type="aff" rid="aff3">
<sup>3</sup>
</xref>
<xref ref-type="aff" rid="aff4">
<sup>4</sup>
</xref>
<xref ref-type="corresp" rid="c001">&#x2a;</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>&#x2020;</sup>
</xref>
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<contrib contrib-type="author" corresp="yes" equal-contrib="yes">
<name>
<surname>Cai</surname>
<given-names>Pei</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="corresp" rid="c001">&#x2a;</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>&#x2020;</sup>
</xref>
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<aff id="aff1">
<sup>1</sup>
<institution>Hunan Provincial Maternal and Child Health Care Hospital</institution>, <addr-line>Changsha</addr-line>, <country>China</country>
</aff>
<aff id="aff2">
<sup>2</sup>
<institution>Department of Pharmacy</institution>, <institution>Xiangya Hospital</institution>, <institution>Central South University</institution>, <addr-line>Changsha</addr-line>, <country>China</country>
</aff>
<aff id="aff3">
<sup>3</sup>
<institution>Hunan Institute for Tuberculosis Control and Hunan Chest Hospital</institution>, <addr-line>Changsha</addr-line>, <country>China</country>
</aff>
<aff id="aff4">
<sup>4</sup>
<institution>Hunan Chest Hospital</institution>, <addr-line>Changsha</addr-line>, <country>China</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>
<bold>Edited by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/387199/overview">Roberto Rodr&#xed;guez-Labrada</ext-link>, Cuban Neuroscience Center, Cuba</p>
</fn>
<fn fn-type="edited-by">
<p>
<bold>Reviewed by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/1554692/overview">Md. Siddiqul Islam</ext-link>, Southeast University, Bangladesh</p>
<p>
<ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/737805/overview">Mukerrem Betul Yerer Aycan</ext-link>, Erciyes University, T&#xfc;rkiye</p>
</fn>
<corresp id="c001">&#x2a;Correspondence: Pei Cai, <email>caipei19850104@126.com</email>; Zheng Deng, <email>zrsuiyue@sina.com</email>
</corresp>
<fn fn-type="equal" id="fn001">
<label>
<sup>&#x2020;</sup>
</label>
<p>These authors have contributed equally to this work</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>21</day>
<month>08</month>
<year>2024</year>
</pub-date>
<pub-date pub-type="collection">
<year>2024</year>
</pub-date>
<volume>15</volume>
<elocation-id>1445328</elocation-id>
<history>
<date date-type="received">
<day>07</day>
<month>06</month>
<year>2024</year>
</date>
<date date-type="accepted">
<day>05</day>
<month>08</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2024 Zheng, Tang, Deng and Cai.</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>Zheng, Tang, Deng and Cai</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<sec>
<title>Background</title>
<p>Platinum-based chemotherapy bring severe hematological toxicity that can lead to dose reduction or discontinuation of therapy. Genetic variations have been reported to influence the risk and extent of hematological toxicity; however, the results are controversial and a comprehensive overview is lacking. This systematic review aimed to identify genetic biomarkers of platinum-induced hematological toxicity.</p>
</sec>
<sec>
<title>Method</title>
<p>Pubmed, Embase and Web of science database were systematically reviewed for studies that evaluated the association of genetic variants and platinum-related hematological toxicity in tumor patients with no prior history of chemotherapy or radiation, published from inception to the 28th of January 2022. The studies should have specific toxicity scoring system as well as defined toxicity end-point. The quality of reporting was assessed using the Strengthening the Reporting of Genetic Association Studies (STREGA) checklist. Results were summarized using narrative synthesis.</p>
</sec>
<sec>
<title>Results</title>
<p>83 studies were eligible with over 682 single-nucleotide polymorphisms across 110 genes. The results are inconsistent and diverse with methodological issues including insufficient sample size, population stratification, various treatment schedule and toxicity end-point, and inappropriate statistics. 11 SNPs from 10 genes (<italic>ABCB1 rs1128503, GSTP1 rs1695, GSTM1 gene deletion, ERCC1 rs11615, ERCC1 rs3212986, ERCC2 rs238406, XPC rs2228001, XPCC1 rs25487, MTHFR rs1801133, MDM2 rs2279744, TP53 rs1042522</italic>) had consistent results in more than two independent populations. Among them, <italic>GSTP1</italic> rs1695, <italic>ERCC1</italic> rs11615, <italic>ERCC1</italic> rs3212986, and <italic>XRCC1</italic> rs25487 present the most promising results.</p>
</sec>
<sec>
<title>Conclusion</title>
<p>Even though the results are inconsistent and several methodological concerns exist, this systematic review identified several genetic variations that deserve validation in well-defined studies with larger sample size and robust methodology.</p>
</sec>
<sec>
<title>Systematic Review Registration</title>
<p>
<ext-link ext-link-type="uri" xlink:href="https://www.crd.york.ac.uk/">https://www.crd.york.ac.uk/</ext-link>, identifier CRD42021234164.</p>
</sec>
</abstract>
<kwd-group>
<kwd>platinum</kwd>
<kwd>chemotherapy</kwd>
<kwd>hematological toxicity</kwd>
<kwd>polymorphisms</kwd>
<kwd>pharmacogenomics</kwd>
</kwd-group>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Pharmacogenetics and Pharmacogenomics</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec id="s1">
<title>1 Introduction</title>
<p>Platinum agents, including cisplatin, carboplatin and oxaliplatin, are used effectively against various tumor diseases either as monotherapy or in combination with other chemotherapeutics, radiation therapy and/or surgery. However, they display a range of severe side effects due to their poor selectivity for cancerous tissue over normal tissue. Hematological toxicity caused by platinum drugs are those that affect bone marrow function and blood cell production, characterized by leukopenia, neutropenia, thrombocytopenia, and anemia (<xref ref-type="bibr" rid="B87">Oun et al., 2018</xref>). Leukopenia or neutropenia, can leave patients susceptible to infections. Platinum-induced anemia is persisting erythropoietin deficiency state correlated with renal tubular dysfunction (<xref ref-type="bibr" rid="B127">Wood and Hrushesky, 1995</xref>). Acute myelosuppression occurs shortly after chemotherapy, while residual bone marrow injury manifested by a decrease in hematopoietic stem cell reserves or a myelodysplastic syndrome (<xref ref-type="bibr" rid="B121">Wang et al., 2006</xref>).</p>
<p>All three platinum drugs can cause some form of hematological toxicity, and myelosuppression is the dose-limiting toxicity of carboplatin. In the majority of cases, neither cisplatin nor oxaliplatin is associated with severe myelosuppression (<xref ref-type="bibr" rid="B99">Rabik and Dolan, 2007</xref>). Carboplatin induced myelosuppression resulted in neutropenia and thrombocytopenia. Severe (grade 3 or 4) neutropenia occurs in approximately 18% of carboplatin-treated patients, whereas severe thrombocytopenia occurs in approximately 25% of cases (<xref ref-type="bibr" rid="B36">Go and Adjei, 1999</xref>). Cisplatin-induced hematological toxicity is usually mild at intermittent doses of 50&#x2013;60&#xa0;mg/m<sup>2</sup> and myelosuppression presents in 25%&#x2013;30% of patients (<xref ref-type="bibr" rid="B93">Prestayko et al., 1979</xref>). Myelosuppression caused by oxaliplatin is generally mild. Grade 3/4 anemia, neutropenia and thrombocytopenia are observed in only 2%&#x2013;3% of patients (<xref ref-type="bibr" rid="B45">Hartmann and Lipp, 2003</xref>). Hematological toxicity aggravates when platinum agents were combined with other cytotoxic drugs. The degree of hematological toxicity varies upon different chemotherapy regimen. For example, hematological toxicity was more profound in lung cancer patients treated with platinum agents plus gemcitabine (<xref ref-type="bibr" rid="B31">Fisher and D&#x2019;Orazio, 2000</xref>; <xref ref-type="bibr" rid="B103">Schiller et al., 2002</xref>).</p>
<p>Inhibition of cell proliferation is one of the major causes of platinum-induced myelosuppression and related complications. The cytotoxicity of platinum on hematopoietic stem cells is attributed to its highly reactive hydrated platinum complex that binds to DNA and form intra- and inter-strand crosslinks; thereby produce subsequent interference with DNA transcription and/or DNA replication (<xref ref-type="bibr" rid="B21">Das et al., 2008</xref>). The generation in oxidative stress is also responsible for platinum-induced bone marrow toxicity (<xref ref-type="bibr" rid="B1">Basu et al., 2015</xref>). Increased platinum influx, decreased platinum efflux, impaired cell detoxification, low or absent DNA damage repair and activated cell death signaling may be the reasons of platinum-induced hematological toxicity (<xref ref-type="bibr" rid="B106">Shaloam and Paul, 2014</xref>) (<xref ref-type="fig" rid="F1">Figure 1</xref>).</p>
<fig id="F1" position="float">
<label>FIGURE 1</label>
<caption>
<p>Mechanism of platinum-induced hematological toxicity. (The figure was made by Figdraw) Abbreviations: BER, base excision repair; DSB, double strand break repair; FA, fanconi anemia pathway; MMR, mismatch repair; NER, nucleotide excision repair; TLS, translesion DNA synthesis.</p>
</caption>
<graphic xlink:href="fphar-15-1445328-g001.tif"/>
</fig>
<p>Identifying patients at greatest risk for these complications would be clinically useful for selecting patients for chemotherapy and planning the frequency of monitor and clinical treatment with colony-stimulating factor. Risk factors for hematological toxicities include kidney function, age, drug doses, combination chemotherapy, a poor performance status and prior chemotherapy exposure (<xref ref-type="bibr" rid="B45">Hartmann and Lipp, 2003</xref>; <xref ref-type="bibr" rid="B88">Ouyang et al., 2013</xref>). Furthermore, genetic variations in genes encoding proteins involved in pharmacokinetic and pharmacodynamic processes influence the occurrence and extent of adverse reactions (<xref ref-type="bibr" rid="B143">Zheng et al., 2020</xref>). Although several genetic polymorphisms have been identified to influence platinum-induced hematological toxicity, a comprehensive overview is lacking. We here provide an overview to identify which genetic variants consistently associated with hematological toxicity and discuss limitations of current pharmacogenetic analyses and formulate directions for further research.</p>
</sec>
<sec sec-type="methods" id="s2">
<title>2 Methods</title>
<sec id="s2-1">
<title>2.1 Study eligibility</title>
<p>The systematic review was reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) checklist (<xref ref-type="bibr" rid="B89">Page et al., 2021</xref>) (<xref ref-type="sec" rid="s11">Supplementary Table S1</xref>). The protocol was registered in the international prospective register of systematic reviews (PROSPERO; Registered number: CRD42021234164). The inclusion criteria were (<xref ref-type="bibr" rid="B87">Oun et al., 2018</xref>): studies that focus on the association between hematological toxicity and genetic polymorphisms (<xref ref-type="bibr" rid="B127">Wood and Hrushesky, 1995</xref>); studies including cancer patients using platinum-containing chemotherapy (<xref ref-type="bibr" rid="B121">Wang et al., 2006</xref>); studies that have specific toxicity scoring system and defined toxicity end-point. The exclusion criteria include the followings (<xref ref-type="bibr" rid="B87">Oun et al., 2018</xref>): preclinical studies (animal experiment or <italic>in vitro</italic> studies) (<xref ref-type="bibr" rid="B127">Wood and Hrushesky, 1995</xref>); studies in which patients were treated with concurrent radiotherapy (<xref ref-type="bibr" rid="B121">Wang et al., 2006</xref>); studies that were non-English, case report, review or meta-analysis (<xref ref-type="bibr" rid="B99">Rabik and Dolan, 2007</xref>); studies in which patients have prior history of chemotherapy and/or radiation.</p>
</sec>
<sec id="s2-2">
<title>2.2 Search strategy</title>
<p>PubMed/MEDLINE, EMBASE and Web of Science were searched for publications from inception to the 28th of January 2022. The literature search was conducted using Medical Subject Headings and combinations of relevant keywords. The detailed search strategy can be found in <xref ref-type="sec" rid="s11">Supplementary Table S2</xref>. Additional research papers were identified by screening the reference sections of included articles. Two authors (YZ and MT) independently performed the data screening. Disagreements were consulted with a third arbiter (ZD).</p>
</sec>
<sec id="s2-3">
<title>2.3 Quality assessment</title>
<p>The quality of the studies will be assessed using a scoring system modified from a previously published study (<xref ref-type="bibr" rid="B66">Leusink et al., 2016</xref>) based on STREGA recommendations (<xref ref-type="bibr" rid="B71">Little et al., 2009</xref>) <xref ref-type="sec" rid="s11">Supplementary Table S3</xref>. The scoring system contains ten items on five domains: clinical information, genotyping, study population origin, sample size and statistical correction for multiple testing, and study analysis. Each study included in this review was assessed for quality as good (overall quality score:7-10), moderate (overall quality score:4-6), or poor (overall quality score&#x2264;3) based on scores. Two reviewers (YZ and MT) will assess the quality independently and a third reviewer (PC) will be consulted in case of disagreement.</p>
</sec>
<sec id="s2-4">
<title>2.4 Data collection and analysis</title>
<p>The following data were extracted from each publication by two authors (YZ and MT): author, year, source of study (reference), sample size, ethnicity, type of cancer, number of treatment cycles, treatment schedule, toxicity scoring system, defined toxicity end-point, genetic polymorphisms involved and main study results.</p>
<p>Due to the heterogeneity in the patient population, treatment schedule, outcome definitions, meta-analysis was not appropriate. Studies were analyzed using a narrative synthesis approach.</p>
</sec>
</sec>
<sec sec-type="results" id="s3">
<title>3 Results</title>
<sec id="s3-1">
<title>3.1 Study selection</title>
<p>The initial search delivered 2057 articles; after removal of duplicates, 1156 abstracts were primarily screened of which 207 full-text articles remained. After reading the full-text, 83 studies were eventually included in the present systematic review. The article selection process is shown in <xref ref-type="fig" rid="F2">Figure 2</xref>.</p>
<fig id="F2" position="float">
<label>FIGURE 2</label>
<caption>
<p>Flow diagram for study selection.</p>
</caption>
<graphic xlink:href="fphar-15-1445328-g002.tif"/>
</fig>
</sec>
<sec id="s3-2">
<title>3.2 Study characteristics and quality assessment</title>
<p>The study characteristics of the 83 included articles are shown in <xref ref-type="table" rid="T1">Table 1</xref>, <xref ref-type="sec" rid="s11">Supplementary Tables S4, S5</xref>. 75 studies were candidate gene studies. Three studies were genome-wide association studies (GWAS) (<xref ref-type="bibr" rid="B74">Low et al., 2013</xref>; <xref ref-type="bibr" rid="B49">Huang et al., 2015</xref>; <xref ref-type="bibr" rid="B10">Cao et al., 2016</xref>), three studies were whole-exome sequencing (<xref ref-type="bibr" rid="B40">Gr&#xe9;en et al., 2016</xref>; <xref ref-type="bibr" rid="B110">Svedberg et al., 2020</xref>; <xref ref-type="bibr" rid="B4">Bj&#xf6;rn et al., 2020a</xref>). 1 study was whole-genome sequencing (WGS) (<xref ref-type="bibr" rid="B3">Bj&#xf6;rn et al., 2020b</xref>). 1 study used targeted resequencing of 100 pharmacokinetics-related genes (<xref ref-type="bibr" rid="B135">Yoshihama et al., 2018</xref>).</p>
<table-wrap id="T1" position="float">
<label>TABLE 1</label>
<caption>
<p>Overview of pharmacogenetic studies on platinum-induced hematological toxicity.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="left">Authors, Year</th>
<th align="left">Sample size cancer</th>
<th align="left">Treatment</th>
<th align="left">
<italic>Gene</italic>
</th>
<th align="left">Toxicity endpoint</th>
<th align="left">SNPs with significant association)</th>
<th align="left">Total score</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left">
<xref ref-type="bibr" rid="B50">Isla et al. (2004)</xref>
</td>
<td align="left">62 NSCLC</td>
<td align="left">DDP &#x2b; TXT</td>
<td align="left">
<italic>ERCC1, XPD, RRM1, MDR1</italic>
</td>
<td align="left">Grade 2-4 anemia, leukopenia, neutropenia and thrombocytopenia</td>
<td align="left">
<italic>ERCC2/XPD</italic> rs13181 (Lys751Gln), <italic>RRM1</italic> rs12806698(-37C/A)</td>
<td align="left">2</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B44">Han et al. (2007)</xref>
</td>
<td align="left">107 NSCLC</td>
<td align="left">DDP &#x2b; CPT-11</td>
<td align="left">
<italic>ABCB1, ABCC2, ABCG2</italic>
</td>
<td align="left">Grade 4 neutropenia</td>
<td align="left">
<italic>ABCB1/MDR1</italic> rs2032582 (G2677TA)</td>
<td align="left">2</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B61">Kimcurran et al. (2011)</xref>
</td>
<td align="left">300 NSCLC</td>
<td align="left">DDP/CBP &#x2b; GEM/NVB/PTX</td>
<td align="left">
<italic>ERCC1</italic>
</td>
<td align="left">Grade 1-3 hematologic toxicity</td>
<td align="left">No significant association</td>
<td align="left">4</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B79">Marsh et al. (2007)</xref>
</td>
<td align="left">914 (Discovery cohort and validation cohort in ratio 2:1)<break/>Ovarian cancer</td>
<td align="left">CBP &#x2b; PTX/TXT</td>
<td align="left">
<italic>ERCC1, XPD, XRCC1, ABCB1(MDR1), ABCC1, ABCC2, ABCG2, GSTP1, MAPT, MPO, TP53</italic>
</td>
<td align="left">Grade 4 neutropenic toxicity</td>
<td align="left">No significant association</td>
<td align="left">4</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B113">Tibaldi et al. (2008)</xref>
</td>
<td align="left">65 NSCLC</td>
<td align="left">DDP &#x2b; GEM</td>
<td align="left">
<italic>ERCC1, XPD</italic>
</td>
<td align="left">Grade 3-4 neutropenia, thrombocytopenia and anemia</td>
<td align="left">No significant association</td>
<td align="left">3</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B123">Wang et al. (2008)</xref>
</td>
<td align="left">139 NSCLC &#x2b; SCLC</td>
<td align="left">DDP &#x2b; NVB/PTX/TXT/GEM/VP-16</td>
<td align="left">
<italic>XPCC1</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity</td>
<td align="left">No significant association</td>
<td align="left">4</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B58">Kim et al. (2009)</xref>
</td>
<td align="left">118 Epithelial ovarian cancer</td>
<td align="left">DDP/CBP &#x2b; PTX CBP &#x2b; TXT</td>
<td align="left">
<italic>ERCC1, ERCC2, XRCC1, ABCB1, GSTP1, GSTM1, GSTT1</italic>
</td>
<td align="left">Grade 3-4 hematological toxicity</td>
<td align="left">
<italic>GSTP1</italic> rs1695 (A313G, Ile105Val)</td>
<td align="left">5</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B105">Seo et al. (2009)</xref>
</td>
<td align="left">75 Gastric cancer</td>
<td align="left">L-OHP &#x2b; 5-FU &#x2b; LV</td>
<td align="left">
<italic>ERCC1, GSTT1, GSTM1, GSTP1</italic>
</td>
<td align="left">Grade 3-4 neutropenia</td>
<td align="left">No significant association</td>
<td align="left">3</td>
</tr>
<tr>
<td align="left">(<xref ref-type="bibr" rid="B128">Wu et al. 2009</xref>)</td>
<td align="left">209 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOthers DDP/CBP combinations</td>
<td align="left">
<italic>XPD</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity, leukocytopenia, anemia and thrombocytopenia</td>
<td align="left">
<italic>XPD</italic> rs238406 (C22541A, Arg156Arg)</td>
<td align="left">7</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B15">Chen et al. (2010)</xref>
</td>
<td align="left">95 NSCLC</td>
<td align="left">DDP &#x2b; GEM/NVB/TXT</td>
<td align="left">
<italic>ERCC1, ABCB1(MDR1)</italic>
</td>
<td align="left">Grade&#x2265;1 hematologic toxicity</td>
<td align="left">No significant association</td>
<td align="left">3</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B34">Giovannetti et al. (2011)</xref>
</td>
<td align="left">122 Pancreatic cancer</td>
<td align="left">PEXG, PDXG, EC-GemCap</td>
<td align="left">
<italic>ERCC1, XPD, XRCC1</italic>
</td>
<td align="left">Grade 1-4 hematological toxicity, Grade 3-4 hematological toxicity</td>
<td align="left">No significant association</td>
<td align="left">5</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B43">Han et al. (2011)</xref>
</td>
<td align="left">445 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOther DDP/CBP combinations</td>
<td align="left">
<italic>ABCC2(MRP2)</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity, anemia, agranulocytosis, leukocytopenia and thrombocytopenia</td>
<td align="left">
<italic>ABCC2/MRP2</italic> rs3740066 (C3972T)</td>
<td align="left">7</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B76">Ludovini et al. (2011)</xref>
</td>
<td align="left">189 NSCLC</td>
<td align="left">DDP &#x2b; GEM/PTX/NVB</td>
<td align="left">
<italic>ERCC1, XRCC3, XPD, P53</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity</td>
<td align="left">No significant association</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B140">Zhao et al. (2012)</xref>
</td>
<td align="left">663 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOthers DDP/CBP combinations</td>
<td align="left">
<italic>MMP-2</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity, neutropenia, anemia and thrombocytopenia</td>
<td align="left">
<italic>MMP-2</italic> rs1477017, <italic>MMP-2</italic> rs17301608, <italic>MMP-2</italic> rs12934241, <italic>MMP-2</italic> rs243847, <italic>MMP-2</italic> rs243844, <italic>MMP-2</italic> rs11639960, <italic>MMP-2</italic> rs199211</td>
<td align="left">8</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B27">Er&#x10d;ulj et al. (2012)</xref>
</td>
<td align="left">94 Malignant mesothelioma</td>
<td align="left">DDP/CBP &#x2b; GEM/PEM<break/>DDP &#x2b; MMC &#x2b; VCR</td>
<td align="left">
<italic>XPD, ERCC1, GSTP1, GSTM1, GSTT1</italic>
</td>
<td align="left">Grade 1-4 thrombocytopenia, Grade 2-4 leukopenia, anemia and neutropenia</td>
<td align="left">
<italic>ERCC2/XPD</italic> rs1799793 (Asp312Asn), <italic>ERCC1</italic> rs3212986 (C8092A), <italic>GSTM1</italic> gene deletion</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B41">Gu et al. (2012)</xref>
</td>
<td align="left">445 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOther DDP/CBP combinations</td>
<td align="left">
<italic>BCL2, BAX, CASP3, CASP8, CASP10, TNFa, MIF</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity</td>
<td align="left">
<italic>CASP3</italic> rs6948 (1296A&#x3e;C, 3&#x2032;-UTR)</td>
<td align="left">8</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B51">Iwata et al. (2012)</xref>
</td>
<td align="left">53 Advanced carcinomas</td>
<td align="left">DDP &#x2b; 5-FU/GEM/TXT/VP-16/PEM/CPT-11</td>
<td align="left">
<italic>OCT2, MATE1</italic>
</td>
<td align="left">Grade 2-4 leukopenia and thrombocytopenia</td>
<td align="left">No significant association</td>
<td align="left">2</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B57">Khrunin et al. (2010)</xref>
</td>
<td align="left">104 Ovarian cancer</td>
<td align="left">DDP &#x2b; CTX</td>
<td align="left">
<italic>GSTA1, GSTM1, GSTM3, GSTP1, GSTT1, ERCC1, XPD, XPCC1, TP53, CYP2E1</italic>
</td>
<td align="left">Grade 3-4 neutropenia, Grade 2-4 anemia, Grade 1-4 thrombocitopenia</td>
<td align="left">
<italic>XPCC1</italic> rs25487 (Arg399Gln), <italic>TP53</italic> rs1042522 (C&#x3e;G, Pro72Arg), <italic>ERCC2/XPD</italic> rs1799793 (Asp312Asn), <italic>GSTM1</italic> gene deletion, <italic>GSTM3</italic> AGG deletion</td>
<td align="left">4</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B96">Qian et al. (2012)</xref>
</td>
<td align="left">279 (in a discovery set) and 384 (in a validation set)<break/>NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOther DDP/CBP combination</td>
<td align="left">
<italic>CASP8, CASP10</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity, leukocytopenia, agranulocytosis, anemia, thrombocytopenia</td>
<td align="left">
<italic>CASP8</italic> rs12990906(A&#x3e;G)</td>
<td align="left">8</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B131">Xu et al. (2012)</xref>
</td>
<td align="left">204 NSCLC</td>
<td align="left">DDP &#x2b; GEM/VP-16/TXT/VDS</td>
<td align="left">
<italic>CTR1</italic>
</td>
<td align="left">Grade 3-4 neutropenia, anemia and thrombocytopenia</td>
<td align="left">No significant association</td>
<td align="left">5</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B138">Zhan et al. (2012)</xref>
</td>
<td align="left">445 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOthers DDP/CBP combinations</td>
<td align="left">
<italic>Hsa-miR-196a2</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity, leukocytopenia, neutropenia, thrombocytopenia and anemia</td>
<td align="left">No significant association</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B19">Cortejoso et al. (2013)</xref>
</td>
<td align="left">106 Colorectal cancer</td>
<td align="left">L-OHP &#x2b; 5-FU &#x2b; LV<break/>L-OHP &#x2b; CAP</td>
<td align="left">
<italic>ABCB1, XRCC1, ERCC1, ERCC2, GSTP1, GSTT1</italic>
</td>
<td align="left">Grade 3-4 hematological toxicity, anemia, neutropenia, neutropenia febrile, leucopenia and thrombocytopenia</td>
<td align="left">
<italic>ERCC1</italic> rs11615 (C118T, Asn118Asn)</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B39">Gori&#x10d;ar et al. (2014)</xref>
</td>
<td align="left">139 Malignant mesothelioma</td>
<td align="left">DDP &#x2b; GEM/PEM<break/>Other DDP doublets</td>
<td align="left">
<italic>REV1, REV3L</italic>
</td>
<td align="left">Grade 2-4 neutropenia, leukopenia, anemia and thrombocytopenia</td>
<td align="left">
<italic>REV1</italic> rs3087403(C&#x3e;T), <italic>REV1</italic> rs3087386(A&#x3e;G)</td>
<td align="left">5</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B65">Lee et al. (2013)</xref>
</td>
<td align="left">292 Colon cancer</td>
<td align="left">L-OHP &#x2b; LV &#x2b; 5-FU</td>
<td align="left">
<italic>MTHFR, ERCC1, XPD, XRCC1, ABCC2, AGXT, GSTP1, GSTT1, GSTM1</italic>
</td>
<td align="left">Grade 3-4 neutropenia, anemia, thrombocytopenia and febrile neutropenia</td>
<td align="left">
<italic>MTHFR</italic> rs1801133(C677T), <italic>ERCC1</italic> rs11615 (C118T, Asn118Asn), <italic>ABCC2/MRP2</italic> rs717620 (C-24T)</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B68">Li et al. (2014)</xref>
</td>
<td align="left">1004 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOther DDP/CBP combinations</td>
<td align="left">
<italic>MTHFR</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity, neutropenia, leucopenia, anemia and thrombocytopenia</td>
<td align="left">
<italic>MTHFR</italic> rs1537514(G&#x3e;C), <italic>MTHFR</italic> rs1801133(C677T)</td>
<td align="left">8</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B74">Low et al. (2013)</xref>
</td>
<td align="left">1171 Carcinomas</td>
<td align="left">DDP/CBP-based chemotherapy</td>
<td align="left">GWAS</td>
<td align="left">Grade 3-4 neutropenia/leucopenia</td>
<td align="left">rs4886670 near <italic>RPL36AP45</italic>; rs10253216 near AGR2, rs11071200 on <italic>PRTG</italic>
</td>
<td align="left">5</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B91">Peng et al. (2013)</xref>
</td>
<td align="left">663 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOther DDP/CBP combinations</td>
<td align="left">
<italic>VCP</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity, neutropenia, anemia and thrombocytopenia</td>
<td align="left">
<italic>VCP</italic> rs2074549</td>
<td align="left">7</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B18">Corrigan et al. (2014)</xref>
</td>
<td align="left">136 NSCLC<break/>Malignant mesothelioma</td>
<td align="left">DDP/CBP &#x2b; PEM</td>
<td align="left">
<italic>MTHFR, ERCC2</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity and neutropaenia</td>
<td align="left">No significant association</td>
<td align="left">8</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B8">Cai et al. (2014)</xref>
</td>
<td align="left">663 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/VP-16/BEV</td>
<td align="left">
<italic>CDC25A, CDC25B, CDC25C</italic>
</td>
<td align="left">Grade 3-4 hematology toxicity</td>
<td align="left">
<italic>CDC25B</italic> rs3761218</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B13">Chen et al. (2014)</xref>
</td>
<td align="left">412 NSCLC &#x2b; SCLC</td>
<td align="left">DDP/CBP &#x2b; GEM/PTX/NVB/VP-16/CPT-11</td>
<td align="left">
<italic>WISP1</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity</td>
<td align="left">
<italic>WISP1</italic> rs16904853, <italic>WISP1</italic> rs2929970, <italic>WISP1</italic> rs2977549, <italic>WISP1</italic> rs2977551</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B56">Kanazawa et al. (2014)</xref>
</td>
<td align="left">41 Non-squamous non-small cell lung cancer</td>
<td align="left">CBP &#x2b; PEM</td>
<td align="left">
<italic>MTHFR</italic>
</td>
<td align="left">Grade 3-4 leukopenia, neutropenia, anemia and thrombocytopenia</td>
<td align="left">No significant association</td>
<td align="left">4</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B92">Peng et al. (2014)</xref>
</td>
<td align="left">235 NSCLC</td>
<td align="left">DDP &#x2b; PTX/GEM/NVB/PEM</td>
<td align="left">
<italic>OGG1, APE1, XPCC1</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity</td>
<td align="left">
<italic>XPCC1</italic> rs25487</td>
<td align="left">7</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B101">Ruzzo et al. (2014)</xref>
</td>
<td align="left">517 Colorectal cancer</td>
<td align="left">L-OHP &#x2b; 5-FU &#x2b; LV<break/>L-OHP &#x2b; CAP</td>
<td align="left">
<italic>MTHFR, ERCC1, XRCC1, XPD, XRCC3, GST-PI, GST-T1, GST-M1, ABCC1, ABCC2</italic>
</td>
<td align="left">Grade 3-4 neutropenia</td>
<td align="left">No significant association</td>
<td align="left">7</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B107">Shao et al. (2014)</xref>
</td>
<td align="left">663 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOther DDP/CBP combinations</td>
<td align="left">
<italic>POLK</italic>
</td>
<td align="left">Grade 3-4 hematological toxicity, anemia, agranulocytosis, leukocytopenia and thrombocytopenia</td>
<td align="left">
<italic>POLK</italic> rs3756558</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B111">Tan et al. (2014)</xref>
</td>
<td align="left">1004 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOthers DDP/CBP combinations</td>
<td align="left">
<italic>MIF, JAB1, SKP1, CUL1, RBX1, NEDD8, CAND1, CD74</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity, neutropenia, leucopenia, anemia and thrombocytopenia</td>
<td align="left">
<italic>MIF</italic> rs482244 (G&#x3e;A), <italic>MIF</italic> rs4822446(A&#x3e;G), <italic>MIF</italic> rs12485068(A&#x3e;G), <italic>CD74</italic> rs2748249(C&#x3e;A), <italic>CD74</italic> rs1560661(G&#x3e;A)</td>
<td align="left">7</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B120">Wang et al. (2014)</xref>
</td>
<td align="left">119 SCLC</td>
<td align="left">DDP &#x2b; VP-16</td>
<td align="left">
<italic>MDM2, TP53</italic>
</td>
<td align="left">Grade 3-4 neutropenia</td>
<td align="left">
<italic>MDM2</italic> rs2279744, <italic>TP53</italic> rs1042522</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B139">Zhao et al. (2015)</xref>
</td>
<td align="left">1004 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOthers DDP/CBP combinations</td>
<td align="left">
<italic>TERT</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity, neutropenia, anemia and thrombocytopenia</td>
<td align="left">No significant association</td>
<td align="left">8</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B141">Zheng et al. (2014)</xref>
</td>
<td align="left">444 NSCLC</td>
<td align="left">DDP/CBP &#x2b; GEM/VP-16/PTX/PEM<break/>Other</td>
<td align="left">
<italic>TP53, MDM2</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity</td>
<td align="left">
<italic>MDM2</italic> rs937282</td>
<td align="left">7</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B10">Cao et al. (2016)</xref>
</td>
<td align="left">333 (in discovery cohort) and 876 (in validation cohort) NSCLC</td>
<td align="left">DDP/CBP &#x2b; GEM/PTX/TXT</td>
<td align="left">GWAS</td>
<td align="left">Grade 3-4 myelosuppression</td>
<td align="left">rs13014982<font color="#FE0191">&#xa0;</font>at 2q24.3, rs9909179<font color="#FE0191">&#xa0;</font>at 17p12</td>
<td align="left">7</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B12">Chen et al. (2016)</xref>
</td>
<td align="left">317 NSCLC &#x2b; SCLC</td>
<td align="left">DDP/CBP &#x2b; GEM/PTX/NVB/VP-16/CPT-11</td>
<td align="left">
<italic>ABCB1, ABCG2, AQP2, AQP9, MVP, OCT2, SIRT1, SLC2A1, TMEM205, HMGB2, RPA1, SSRP1, XPA, XRCC5</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity</td>
<td align="left">
<italic>XRCC5</italic> rs1051685, <italic>XRCC5</italic> rs6941, <italic>AQP2</italic> rs10875989</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B23">Deng et al. (2015)</xref>
</td>
<td align="left">97 NSCLC</td>
<td align="left">DDP &#x2b; GEM/NVB/PTX/TXT</td>
<td align="left">
<italic>XPCC1, GSTP1, ATP7A</italic>
</td>
<td align="left">Grade 1-4 lymphopenia, leukopenia, neutropenia, thrombocytopenia and anemia</td>
<td align="left">
<italic>XRCC1</italic> rs25487(G23885A, Arg399Gln)</td>
<td align="left">5</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B40">Gr&#xe9;en et al. (2016)</xref>
</td>
<td align="left">32(in discovery cohort) and 291(in validation cohort) NSCLC</td>
<td align="left">CBP &#x2b; GEM</td>
<td align="left">Whole-Exome Sequencing</td>
<td align="left">Grade 3-4 neutropenia, thrombocytopenia</td>
<td align="left">rs1453542 in <italic>OR4D6</italic>, rs5925720 in <italic>DDX53</italic>
</td>
<td align="left">7</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B49">Huang et al. (2015)</xref>
</td>
<td align="left">286 Cervical cancer</td>
<td align="left">DDP/CBP &#x2b; taxanes/CPT-11</td>
<td align="left">
<italic>GWAS</italic>
</td>
<td align="left">Grade 2-4 neutropenia</td>
<td align="left">32 variants</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B55">Kalikaki et al. (2015)</xref>
</td>
<td align="left">107 NSCLC</td>
<td align="left">DDP/CBP &#x2b; PTX/GEMDDP &#x2b; TXT/NVB</td>
<td align="left">
<italic>ERCC1, XPD, XRCC1</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity</td>
<td align="left">No significant association</td>
<td align="left">4</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B63">Lambrechts et al. (2015)</xref>
</td>
<td align="left">290 Ovarian cancer</td>
<td align="left">CBP &#x2b; PTX<break/>CBP mono-therapy</td>
<td align="left">
<italic>ABCB1, ABCC1, ABCC2, ABCG2, TP53, GSTP1, ERCC1, ERCC2</italic>
</td>
<td align="left">Grade 3-4 anemia, thrombocytopenia and febrile neutropenia, Grade 4 neutropenia</td>
<td align="left">
<italic>ABCB1/MDR1</italic> rs1128503 (C1236T), <italic>ABCC2/MRP2</italic> rs12762549 (&#x2a;&#x2b;9383C&#x3e;G), <italic>ERCC1</italic> rs11615 (C118T, Asn118Asn)</td>
<td align="left">8</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B95">Qian et al. (2015)</xref>
</td>
<td align="left">663 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXT<break/>Other combinations</td>
<td align="left">
<italic>MDM2</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity</td>
<td align="left">
<italic>MDM2</italic> rs1470383(G&#x3e;A)</td>
<td align="left">7</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B132">Ye et al. (2015)</xref>
</td>
<td align="left">663 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOthers DDP/CBP combinations</td>
<td align="left">
<italic>REV3, REV7</italic>
</td>
<td align="left">Grade 3-4 hematological toxicity, anemia, agranulocytosis, leukocytopenia and thrombocytopenia</td>
<td align="left">
<italic>REV3</italic> rs240966, <italic>REV3</italic> rs4945880(G&#x3e;A), <italic>REV3</italic> rs465646(G&#x3e;A), <italic>REV7</italic> rs2233025(G&#x3e;A)</td>
<td align="left">7</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B134">Yin et al. (2015)</xref>
</td>
<td align="left">325 NSCLC</td>
<td align="left">DDP/CBP &#x2b; GEM/VP-16/PTX/PEM<break/>Other</td>
<td align="left">
<italic>eIF3a</italic>
</td>
<td align="left">Grade 1-4 neutropenia, anemia and thrombocytopenia</td>
<td align="left">
<italic>eIF3a</italic> rs1409314, <italic>eIF3a</italic> rs4752219, <italic>eIF3a</italic> rs4752220, <italic>eIF3a</italic> rs7091672</td>
<td align="left">5</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B16">Chu et al. (2016)</xref>
</td>
<td align="left">1021 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOther DDP/CBP combinations</td>
<td align="left">
<italic>Rad18</italic>
</td>
<td align="left">Grade 3-4 hematological toxicity, anemia, agranulocytosis, leukocytopenia and thrombocytopenia</td>
<td align="left">No association in the whole population. Significant association in subgroup: <italic>RAD18</italic> rs586014(A&#x3e;G), <italic>RAD18</italic> rs654448(G&#x3e;A), <italic>RAD18</italic> rs9880051(G&#x3e;A), <italic>RAD18</italic> rs6763823(G&#x3e;A)</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B28">Fang et al. (2017)</xref>
</td>
<td align="left">408 NSCLC &#x2b; SCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/TXT/VP-16</td>
<td align="left">
<italic>miR-605, miR-146a, miR-149, miR-196a-2, miR-27a, miR-499, miR-30c-1, miR-5197</italic>
</td>
<td align="left">Grade 3-4 haematologic toxicity</td>
<td align="left">No association in the whole population. Significant association in subgroup: <italic>miR-5197</italic> rs2042253</td>
<td align="left">7</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B42">Guo et al. (2016)</xref>
</td>
<td align="left">292 Lung adenocarcinoma</td>
<td align="left">DDP/CBP combinations</td>
<td align="left">
<italic>p53, MDM2</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity</td>
<td align="left">
<italic>MDM2</italic> rs2279744 (309T&#x3e;G)</td>
<td align="left">5</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B48">Hu et al. (2016)</xref>
</td>
<td align="left">467 NSCLC &#x2b; SCLC</td>
<td align="left">DDP/CBP &#x2b; GEM/VP-16/PEM/TXT/PTX/CPT-11/NVB</td>
<td align="left">
<italic>CASC8</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity</td>
<td align="left">No significant association in overall subjects.<break/>Significant association in subgroup: <italic>CASC8</italic> rs10505477</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B53">Jia et al. (2016)</xref>
</td>
<td align="left">345 (in discovery group) and 344 (in replication group) NSCLC</td>
<td align="left">DDP/CBP &#x2b; PEM/TXT/PTX/GEM</td>
<td align="left">
<italic>GADD45A, GADD45B, GADD45G, MAP2K7, MAP2K4, MAP3K4, MAPK8, MAPK9, MAPK14</italic>
</td>
<td align="left">Grade 2-4 leukopenia, neutropenia, thrombocytopenia and anemia</td>
<td align="left">
<italic>GADD45B</italic> rs2024144(C&#x3e;T), <italic>GADD45B</italic> rs2024144(C&#x3e;T), <italic>GADD45B</italic> rs2024144(C&#x3e;T)</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B62">Kumpiro et al. (2016)</xref>
</td>
<td align="left">32 NSCLC</td>
<td align="left">CBP &#x2b; GEM</td>
<td align="left">
<italic>CTR1</italic>
</td>
<td align="left">Grade 1-4 anemia, thrombocytopenia and neutropenia</td>
<td align="left">No significant association</td>
<td align="left">3</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B94">Qian et al. (2016)</xref>
</td>
<td align="left">403 NSCLC</td>
<td align="left">DDP/CBP &#x2b; GEM/PEM/PTX/TXT/NVB</td>
<td align="left">
<italic>OCT2, ABCB1, ABCC2(MRP2), MATE1</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity</td>
<td align="left">
<italic>OCT2</italic> rs316019 (808G/T, p.270Ala &#x3e; Ser), <italic>MATE1</italic> rs2289669</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B108">Song et al. (2017)</xref>
</td>
<td align="left">1004 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOthers DDP/CBP combinations</td>
<td align="left">
<italic>XPC, RAD23B, ERCC2, GTF2H1, XPA, ERCC5, ERCC1, ERCC4, ERCC8, ERCC, DDB2, LIG1, CDK7, CCNH, MNAT1, RPA1, RPA2, RFC1, RFC2, POLD1, POLD2, POLD3, POLD4, POLE, POLE2, GTF2H3, GTF2H4</italic>
</td>
<td align="left">Grade 3-4 anemia, neutropenia and trombocytopenia</td>
<td align="left">No SNPs satisfied the significant level of bonferroni correction<break/>
<italic>GTF2H1</italic> rs4150558, <italic>POLD3</italic> rs10857, <italic>POLD3</italic> rs6592576, <italic>RPA1</italic> rs12727, <italic>POLD1</italic> rs3219281, <italic>POLD1</italic> rs3219341, <italic>POLD1</italic> rs1726801</td>
<td align="left">5</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B119">Wang et al. (2016)</xref>
</td>
<td align="left">1004 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOthers DDP/CBP combinations</td>
<td align="left">
<italic>RICTOR</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity, anemia, neutropenia and thrombocytopenia</td>
<td align="left">
<italic>RICTOR</italic> rs7703002, <italic>RICTOR</italic> rs4321771</td>
<td align="left">8</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B130">Xu et al. (2016)</xref>
</td>
<td align="left">272 female patients NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOthers DDP/CBP combinations</td>
<td align="left">
<italic>CHEK2</italic>
</td>
<td align="left">Grade 3-4 hematological toxicity and leukotoxicity</td>
<td align="left">No significant association</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B133">Yin et al. (2016)</xref>
</td>
<td align="left">190 (in Derivation cohort) and 200 (in Derivation cohort) NSCLC</td>
<td align="left">DDP/CBP &#x2b; GEM/PEM/PTX/TXT/NVB/VP-16</td>
<td align="left">416 SNPs in 185 genes</td>
<td align="left">Grade 3-4 hematological toxicity</td>
<td align="left">The hematological toxicity prediction model achieved a sensitivity of 0.89 and a specificity of 0.39 with the ROC AUC of 0.76</td>
<td align="left">5</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B148">Zou et al. (2016)</xref>
</td>
<td align="left">317 NSCLC &#x2b; SCLC</td>
<td align="left">DDP/CBP &#x2b; GEM/PTX/NVB/VP-16/CPT-11</td>
<td align="left">
<italic>HSPA4, HSPB1, HSPE1, RAC1, RhoA</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity</td>
<td align="left">
<italic>RAC1</italic> rs836554, <italic>RAC1</italic> rs4720672</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B38">Gong et al. (2017)</xref>
</td>
<td align="left">467 NSCLC &#x2b; SCLC</td>
<td align="left">DDP/CBP &#x2b; PEM/GEM/PTX/TXT/VP-16Other DDP/CBP-based chemotherapy (CPT-11 &#x2b; DDP/CBP, NVB &#x2b; DDP/CBP)</td>
<td align="left">
<italic>HOTTIP, HOTAIR, H19, ANRIL, CCAT2, MALAT1, MEG3, POLR2E</italic>
</td>
<td align="left">Grade 3-4 hematological toxicity</td>
<td align="left">No association in the whole population significant association in subgroup</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B72">Liu et al. (2017a)</xref>
</td>
<td align="left">555 Lung adenocarcinoma</td>
<td align="left">DDP/CBP &#x2b; PTX/TXT/NVB/VP-16/BEV</td>
<td align="left">
<italic>CASP8</italic>
</td>
<td align="left">Grade 3-4 neutropenia, thrombocytopenia and anemia</td>
<td align="left">
<italic>CASP8</italic> rs7608692(G&#x3e;A)</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B73">Liu et al. (2017b)</xref>
</td>
<td align="left">220 NSCLC &#x2b; SCLC</td>
<td align="left">DDP/CBP &#x2b; GEM/PEM/PTX/TXT/NVB</td>
<td align="left">
<italic>MLH1, MSH2, MSH3, MSH4, MSH5, MSH6</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity</td>
<td align="left">
<italic>MSH3</italic> rs6151627, MSH3 rs6151670, MSH3 rs7709909, MSH5 rs805304</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B144">Zheng et al. (2017)</xref>
</td>
<td align="left">437 (in the discovery cohort) and 781 (in the validation cohort) NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXT/PEM</td>
<td align="left">54 gene</td>
<td align="left">Grade 3-4 hematologic toxicity, leukocytopenia, neutropenia, thrombocytopenia and anemia</td>
<td align="left">
<italic>ERCC1</italic> rs3212986, <italic>ERCC1</italic> rs11615, <italic>RRM1</italic> rs12806698, <italic>XPC</italic> rs2228001, <italic>XPC</italic> rs2228000, <italic>XPF</italic> rs1799801, <italic>XPG</italic> rs1047768, <italic>XPG</italic> rs17655, <italic>APE1</italic> rs1130409, <italic>XRCC1</italic> rs25487, <italic>MDM2</italic> rs2279744, <italic>RAD51</italic> rs1801320, <italic>RAD51</italic> rs12593359</td>
<td align="left">8</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B4">Bj&#xf6;rn et al. (2020a)</xref>
</td>
<td align="left">215 in the discovery cohort) and validated in an independent genome-wide association study NSCLC</td>
<td align="left">CBP &#x2b; GEM</td>
<td align="left">whole-exome sequence</td>
<td align="left">Grade 3-4 thrombocytopenia</td>
<td align="left">These analyses identified 130 SNVs/INDELs and 25 genes associated with thrombocytopenia (<italic>p</italic>-value &#x3c;0.002). Twenty-three SNVs were validated in an independent genome-wide association study (GWAS)</td>
<td align="left">7</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B24">De Troia et al. (2019)</xref>
</td>
<td align="left">82 NSCLC &#x2b; SCLC</td>
<td align="left">DDP/CBP &#x2b; VP-16/NVBDDP &#x2b; GEM/PEM/TXT<break/>DDP monotherapy</td>
<td align="left">
<italic>ABCB1, ABCC2, GSTP1</italic>
</td>
<td align="left">Grade 3-4 hematological toxicity</td>
<td align="left">
<italic>ABCB1/MDR1</italic> rs1045642 (C3435T): decreased risk of grade 3-4 hematological toxicity</td>
<td align="left">5</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B69">Li et al. (2018)</xref>
</td>
<td align="left">427 NSCLC</td>
<td align="left">DDP/CBP &#x2b; GEM/PEM/TXT/NVB/PTX</td>
<td align="left">
<italic>ATP7A, ATP7B</italic>
</td>
<td align="left">Grade 3-4 hematological toxicity</td>
<td align="left">No significant association</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B109">Sun et al. (2018)</xref>
</td>
<td align="left">1004 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOthers DDP/CBP combinations</td>
<td align="left">
<italic>SCL31A1</italic>
</td>
<td align="left">Grade 3-4 hematological toxicity, anemia, neutropenia, leukocytopenia and thrombocytopenia</td>
<td align="left">
<italic>SLC31A1</italic> rs4979223, <italic>SLC31A1</italic> rs4978536, <italic>SLC31A1</italic> rs10817464, <italic>SLC31A1</italic> rs10759637</td>
<td align="left">8</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B135">Yoshihama et al. (2018)</xref>
</td>
<td align="left">320 Ovarian fallopian tube, peritoneal, uterine, or cervical cancer</td>
<td align="left">CBP &#x2b; PTX</td>
<td align="left">
<italic>37 transporters, 30 cytochrome P450 (CYP) enzymes, 10 uridine diphosphate UDPglucuronosyltransferases (UGT), five flavin-containing monooxygenases (FMO), four glutathione S-transferases (GST), four sulfotransferases (SULT), and 10 additional genes</italic>
</td>
<td align="left">Severe hematotoxicity (including neutropenia G4, thrombocytopenia &#x2265; G3, and anemia &#x2265; G3)</td>
<td align="left">
<italic>GSTP1</italic> rs1695</td>
<td align="left">5</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B37">Gong et al. (2019)</xref>
</td>
<td align="left">467 NSCLC &#x2b; SCLC</td>
<td align="left">DDP/CBP &#x2b; PEM/GEM/PTX/TXT/VP-16Other DDP/CBP-based chemotherapy (CPT-11 &#x2b; DDP/CBP, NVB &#x2b; DDP/CBP)</td>
<td align="left">
<italic>STAT3</italic>
</td>
<td align="left">Grade 3-4 hematological toxicity</td>
<td align="left">
<italic>STAT3</italic> rs4796793</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B64">Lavanderos et al. (2019)</xref>
</td>
<td align="left">119 Testicular cancer</td>
<td align="left">DDP &#x2b; BLM &#x2b; VP-16</td>
<td align="left">
<italic>GSTM1, GSTP1, GSTT1, UGT1A1, BLMH, ERCC1, ERCC2, MDR1</italic>
</td>
<td align="left">Grade 3-4 anemia, neutropenia, leukopenia, thrombocytopenia, lymphocytopenia and febrile neutropenia</td>
<td align="left">
<italic>ERCC2/XPD</italic> rs238406 (C22541A, Arg156Arg), <italic>ERCC1</italic> rs11615 (C118T, Asn118Asn)</td>
<td align="left">5</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B70">Liblab et al. (2020)</xref>
</td>
<td align="left">52 Ovarian cancer (Epithelial ovarian cancer)</td>
<td align="left">CBP &#x2b; PTX<break/>CBP mono-therapy</td>
<td align="left">
<italic>ERCC1, XRCC1, GSTP1</italic>
</td>
<td align="left">Grade 2-4 anemia</td>
<td align="left">
<italic>GSTP1</italic> rs1695 (A313G, Ile105Val)</td>
<td align="left">2</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B104">Senk et al. (2019)</xref>
</td>
<td align="left">194 Malignant mesothelioma</td>
<td align="left">DDP &#x2b; GEM/PEM</td>
<td align="left">
<italic>AQP1</italic>
</td>
<td align="left">Grade 2-4 anemia, leukopenia and neutropenia, Grade 1-4 thrombocytopenia</td>
<td align="left">
<italic>AQP1</italic> rs28362731(G&#x3e;A), <italic>AQP1</italic> rs1049305(G&#x3e;C)</td>
<td align="left">5</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B3">Bj&#xf6;rn et al. (2020b)</xref>
</td>
<td align="left">96 (split up into 80% training and 20% validation) NSCLC</td>
<td align="left">CBP &#x2b; GEM</td>
<td align="left">Whole-genome sequencing</td>
<td align="left">Grade 3-4 neutropenia, leukopenia and thrombocytopenia</td>
<td align="left">4594, 5019, and 5066 autosomal SNVs/INDELs</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B7">Bushra et al. (2020)</xref>
</td>
<td align="left">285 NSCLC</td>
<td align="left">DDP/CBP &#x2b; GEM/NVB/PTX/TXT</td>
<td align="left">
<italic>GSTP1, XRCC1, XPC, ERCC1</italic>
</td>
<td align="left">Grade 3-4 anemia, neutropenia, leukopenia and thrombocytopenia</td>
<td align="left">
<italic>GSTP1</italic> rs1695 (A313G, Ile105Val), <italic>XRCC1</italic> rs25487(G23885A, Arg399Gln), <italic>XPC</italic> rs2228001(A&#x3e;C, Lys939Gln)</td>
<td align="left">5</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B30">Ferracini et al. (2021)</xref>
</td>
<td align="left">112 Ovarian cancer (Epithelial ovarian cancer)</td>
<td align="left">CBP &#x2b; PTX<break/>CBP mono-therapy</td>
<td align="left">
<italic>GSTP1, ABCB1</italic>
</td>
<td align="left">Grade 3-4 anemia, neutropenia, Grade 1-4 thrombocytopenia</td>
<td align="left">
<italic>GSTP1</italic> rs1695 (A313G, Ile105Val), <italic>ABCB1/MDR1</italic> rs1128503 (C1236T)</td>
<td align="left">7</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B85">Nomura et al. (2020)</xref>
</td>
<td align="left">158 Esophageal cancer</td>
<td align="left">DDP &#x2b; TXT &#x2b; 5-FU</td>
<td align="left">
<italic>ABCB1, ABCC2, ABCG2, GSTM1, GSTT1, GSTP1</italic>
</td>
<td align="left">Grade 3-4 neutropenia</td>
<td align="left">
<italic>ABCB1/MDR1</italic> rs1045642 (C3435T), <italic>ABCC2/MRP2</italic> rs12762549 (&#x2a;&#x2b;9383C&#x3e;G)</td>
<td align="left">6</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B110">Svedberg et al. (2020)</xref>
</td>
<td align="left">215 (in discovery cohort) and 144 (in validation cohort) NSCLC</td>
<td align="left">CBP &#x2b; GEM</td>
<td align="left">whole-exome sequencing</td>
<td align="left">Grade 3-4 neutropenia and leucopenia</td>
<td align="left">50 and 111 SNVs, and 12 and 20 genes<break/>This study created wGRS models for predicting the risk of chemotherapy-induced hematological toxicity</td>
<td align="left">7</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B84">Nairuz et al. (2021)</xref>
</td>
<td align="left">180 Lung cancer</td>
<td align="left">DDP/CBP &#x2b; VP-16/PTX/TXTCBP &#x2b; GEM/ADM</td>
<td align="left">
<italic>XPD, TP53</italic>
</td>
<td align="left">Grade 3-4 neutropenia, leucopenia, anemia and thrombocytopenia</td>
<td align="left">No significant association</td>
<td align="left">2</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B116">Walia et al. (2021)</xref>
</td>
<td align="left">317 NSCLC &#x2b; SCLC</td>
<td align="left">DDP/CBP &#x2b; PEM/CPT-11/TXT/PTX/GEM</td>
<td align="left">
<italic>GSTP1</italic>
</td>
<td align="left">Grade 3-4 anemia, Grade 1-4 anemia, Grade 2-4 anemia, Grade 1-4 leukopenia, Grade 2-4 leukopenia</td>
<td align="left">
<italic>GSTP1</italic> rs1695</td>
<td align="left">7</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B117">Walia et al. (2022)</xref>
</td>
<td align="left">123 Lung adenocarcinoma cancer</td>
<td align="left">DDP/CBP &#x2b; PEM</td>
<td align="left">
<italic>MTHFR</italic>
</td>
<td align="left">Grade 1-3 neutropenia, Grade 2-3 neutropenia</td>
<td align="left">
<italic>MTHFR</italic> rs1801133</td>
<td align="left">7</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B118">Wang et al. (2021)</xref>
</td>
<td align="left">1004 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOthers DDP/CBP combinations</td>
<td align="left">
<italic>ABCG2</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity, anemia, neutropenia and thrombocytopenia</td>
<td align="left">
<italic>ABCG2</italic> rs12505410, <italic>ABCG2</italic> rs1871744, <italic>ABCG2</italic> rs2231138</td>
<td align="left">7</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B142">Zheng et al. (2021)</xref>
</td>
<td align="left">437 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXT/PEM</td>
<td align="left">
<italic>EPO</italic>
</td>
<td align="left">Grade 3-4 hematologic toxicity, leukocytopenia, neutropenia, thrombocytopenia and anemia</td>
<td align="left">
<italic>EPO</italic> rs1617640</td>
<td align="left">6</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>Abbreviations: ADM, doxorubicin; BEV, bevacizumab; BLM, bleomycin; CAP, capecitabine; CBP, carboplatin; CI, confidence interval; CPT-11, irinotecan; CTCAE, common terminology criteria for adverse events; CTX, cyclophosphamide; DDP, cisplatin; EC-GemCap, epirubicin cisplatin (intra-arterial infusion)-gemcitabine capecitabine; GEM, gemcitabine; L-OHP, oxaliplatin; LV, leucovorin; MMC, mitomycin C; NSCLC, non-small cell lung cancer; NVB, navelbine; OR, odds ratios; PDXG, cisplatin, docetaxel capecitabine, gemcitabine; PEM, pemetrexed; PEXG, cisplatin, epirubicin, capecitabine, gemcitabine; PTX, paclitaxel; SCLC, small cell lung cancer; TXT, docetaxel; VCR, vincristine; VDS, vindesine; VP-16, etoposide; 5-FU, fluorouracil.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<p>59 studies involved a single ethnic group [42 Chinese or Han Chinese, 5 Caucasian (<xref ref-type="bibr" rid="B79">Marsh et al., 2007</xref>; <xref ref-type="bibr" rid="B113">Tibaldi et al., 2008</xref>; <xref ref-type="bibr" rid="B34">Giovannetti et al., 2011</xref>; <xref ref-type="bibr" rid="B76">Ludovini et al., 2011</xref>; <xref ref-type="bibr" rid="B63">Lambrechts et al., 2015</xref>), 4 Japanese (<xref ref-type="bibr" rid="B51">Iwata et al., 2012</xref>; <xref ref-type="bibr" rid="B74">Low et al., 2013</xref>; <xref ref-type="bibr" rid="B135">Yoshihama et al., 2018</xref>; <xref ref-type="bibr" rid="B85">Nomura et al., 2020</xref>), 3 Indian (<xref ref-type="bibr" rid="B101">Ruzzo et al., 2014</xref>; <xref ref-type="bibr" rid="B116">Walia et al., 2021</xref>; <xref ref-type="bibr" rid="B117">Walia et al., 2022</xref>), 2 Korean (<xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>; <xref ref-type="bibr" rid="B65">Lee et al., 2013</xref>), 1 Thai (<xref ref-type="bibr" rid="B62">Kumpiro et al., 2016</xref>), 1 Bangladeshi (<xref ref-type="bibr" rid="B84">Nairuz et al., 2021</xref>) and 1 eastern Slavonic origin (<xref ref-type="bibr" rid="B57">Khrunin et al., 2010</xref>)]. Three studies are mixed ancestry (<xref ref-type="bibr" rid="B18">Corrigan et al., 2014</xref>; <xref ref-type="bibr" rid="B63">Lambrechts et al., 2015</xref>; <xref ref-type="bibr" rid="B30">Ferracini et al., 2021</xref>). 21 studies did not explain how ancestry was determined.</p>
<p>Individual study sizes ranged from 32 to 1171 patients. 12 studies had fewer than 100 subjects. 10 studies involved discovery and replication sets (<xref ref-type="bibr" rid="B79">Marsh et al., 2007</xref>; <xref ref-type="bibr" rid="B96">Qian et al., 2012</xref>; <xref ref-type="bibr" rid="B10">Cao et al., 2016</xref>; <xref ref-type="bibr" rid="B40">Gr&#xe9;en et al., 2016</xref>; <xref ref-type="bibr" rid="B53">Jia et al., 2016</xref>; <xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>).</p>
<p>The studied cancer types were: lung cancer (n &#x3d; 63), ovarian cancer (n &#x3d; 6) (<xref ref-type="bibr" rid="B79">Marsh et al., 2007</xref>; <xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>; <xref ref-type="bibr" rid="B57">Khrunin et al., 2010</xref>; <xref ref-type="bibr" rid="B63">Lambrechts et al., 2015</xref>; <xref ref-type="bibr" rid="B70">Liblab et al., 2020</xref>; <xref ref-type="bibr" rid="B30">Ferracini et al., 2021</xref>), malignant mesothelioma (n &#x3d; 3) (<xref ref-type="bibr" rid="B27">Er&#x10d;ulj et al., 2012</xref>; <xref ref-type="bibr" rid="B39">Gori&#x10d;ar et al., 2014</xref>; <xref ref-type="bibr" rid="B104">Senk et al., 2019</xref>), colorectal cancer (n &#x3d; 3) (<xref ref-type="bibr" rid="B19">Cortejoso et al., 2013</xref>; <xref ref-type="bibr" rid="B101">Ruzzo et al., 2014</xref>), one study each evaluated colon cancer (<xref ref-type="bibr" rid="B65">Lee et al., 2013</xref>), gastric cancer (<xref ref-type="bibr" rid="B105">Seo et al., 2009</xref>), testicular cancer (<xref ref-type="bibr" rid="B65">Lee et al., 2013</xref>), esophageal cancer (<xref ref-type="bibr" rid="B85">Nomura et al., 2020</xref>), cervical cancer (<xref ref-type="bibr" rid="B49">Huang et al., 2015</xref>), pancreatic cancer (<xref ref-type="bibr" rid="B34">Giovannetti et al., 2011</xref>), four studies included various cancer types (<xref ref-type="bibr" rid="B18">Corrigan et al., 2014</xref>; <xref ref-type="bibr" rid="B135">Yoshihama et al., 2018</xref>) or did not mention the cancer type (<xref ref-type="bibr" rid="B74">Low et al., 2013</xref>).</p>
<p>64 studies used mixed combination chemotherapy: cisplatin/carboplatin-based chemotherapy (n &#x3d; 51), cisplatin-based chemotherapy (n &#x3d; 10), carboplatin-based chemotherapy (n &#x3d; 3), 19 study uses single platinum-based chemotherapy. Platinum dosage and cycles varied according the tumor type: mostly cisplatin 75&#xa0;mg/m<sup>2</sup> or carboplatin AUC 5, both administered on day 1 every 3 weeks. The dose of oxaliplatin was 85&#xa0;mg/m<sup>2</sup> or 130&#xa0;mg/m<sup>2</sup> 29 studies did not mention the dose of platinum agents.</p>
<p>47 studies analyzed the whole hematological toxicities. 56 studies analyzed detailed hematologic toxicity (leukopenia, neutropenia, thrombocytopenia or anemia). 20 studies analyzed both of them. Most studies (n &#x3d; 80) use National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), three studies use WHO criteria (<xref ref-type="bibr" rid="B50">Isla et al., 2004</xref>; <xref ref-type="bibr" rid="B15">Chen et al., 2010</xref>; <xref ref-type="bibr" rid="B49">Huang et al., 2015</xref>).</p>
<p>The most used end-point of toxicity was the occurrence of grade &#x2265;3 toxicity (n &#x3d; 66). Other studies used a cut-off value of grade &#x2265;1 (n &#x3d; 12), grade &#x2265;2 (n &#x3d; 11), or grade 4 (n &#x3d; 2) (<xref ref-type="bibr" rid="B44">Han et al., 2007</xref>; <xref ref-type="bibr" rid="B79">Marsh et al., 2007</xref>). One study described severe hematological toxicity including neutropenia G4, thrombocytopenia &#x2265; G3, and anemia &#x2265; G3 (<xref ref-type="bibr" rid="B135">Yoshihama et al., 2018</xref>). Eight studies analyzed more than one end-point of grading (<xref ref-type="bibr" rid="B57">Khrunin et al., 2010</xref>; <xref ref-type="bibr" rid="B34">Giovannetti et al., 2011</xref>; <xref ref-type="bibr" rid="B27">Er&#x10d;ulj et al., 2012</xref>; <xref ref-type="bibr" rid="B63">Lambrechts et al., 2015</xref>; <xref ref-type="bibr" rid="B104">Senk et al., 2019</xref>; <xref ref-type="bibr" rid="B30">Ferracini et al., 2021</xref>; <xref ref-type="bibr" rid="B116">Walia et al., 2021</xref>; <xref ref-type="bibr" rid="B117">Walia et al., 2022</xref>).</p>
<p>Among the 83 included studies, 28 (44.4%) were considered high quality, 46 (55.4%) moderate quality, and 9 (10.8%) were of low quality (<xref ref-type="sec" rid="s11">Supplementary Table S6</xref>), the main reason for low study quality was the absence of calculation of sample size (n &#x3d; 82), no consideration of population stratification (n &#x3d; 80) and lack of statistical correction for multiple testing (n &#x3d; 53).</p>
</sec>
<sec id="s3-3">
<title>3.3 Genetic associations investigated in platinum-induced hematological toxicity</title>
<p>51 variants were analyzed in more than one study (<xref ref-type="table" rid="T2">Tables 2</xref>, <xref ref-type="table" rid="T3">3</xref>; <xref ref-type="sec" rid="s11">Supplementary Table S7</xref>).</p>
<table-wrap id="T2" position="float">
<label>TABLE 2</label>
<caption>
<p>Genetic polymorphisms investigated more than twice for association with platinum-induced hematological toxicity.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th rowspan="2" align="center">Pathway</th>
<th rowspan="2" align="center">Gene</th>
<th rowspan="2" align="center">SNP/deletion</th>
<th rowspan="2" align="center">Total (n)</th>
<th colspan="2" align="center">With association</th>
<th rowspan="2" align="center">Without association</th>
</tr>
<tr>
<th align="center">Increased risk</th>
<th align="center">Decreased risk</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left">Transporter</td>
<td align="left">
<italic>SCL31A1 (CTR1)</italic>
</td>
<td align="left">rs10981699 (C&#x3e;T)</td>
<td align="left">2</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">2 (<xref ref-type="bibr" rid="B44">Han et al., 2007</xref>; <xref ref-type="bibr" rid="B35">Giuliano, 2012</xref>)</td>
</tr>
<tr>
<td align="left">Transporter</td>
<td align="left">
<italic>SCL31A1 (CTR1)</italic>
</td>
<td align="left">rs10817465 (C&#x3e;G)</td>
<td align="left">2</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">2 (<xref ref-type="bibr" rid="B44">Han et al., 2007</xref>; <xref ref-type="bibr" rid="B35">Giuliano, 2012</xref>)</td>
</tr>
<tr>
<td align="left">Transporter</td>
<td align="left">
<italic>SCL31A1 (CTR1)</italic>
</td>
<td align="left">rs12686377 (C&#x3e;A)</td>
<td align="left">2</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">2 (<xref ref-type="bibr" rid="B35">Giuliano, 2012</xref>; <xref ref-type="bibr" rid="B65">Lee et al., 2013</xref>)</td>
</tr>
<tr>
<td align="left">Transporter</td>
<td align="left">
<italic>ABCC2(MRP2)</italic>
</td>
<td align="left">rs717620 (C-24T)</td>
<td align="left">6</td>
<td align="left">0</td>
<td align="left">1 (<xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>)</td>
<td align="left">5 (<xref ref-type="bibr" rid="B50">Isla et al., 2004</xref>; <xref ref-type="bibr" rid="B11">Cara and M Eileen, 2006</xref>; <xref ref-type="bibr" rid="B76">Ludovini et al., 2011</xref>; <xref ref-type="bibr" rid="B131">Xu et al., 2012</xref>; <xref ref-type="bibr" rid="B109">Sun et al., 2018</xref>)</td>
</tr>
<tr>
<td align="left">Transporter</td>
<td align="left">
<italic>ABCC2(MRP2)</italic>
</td>
<td align="left">rs3740066 (C3972T, Ile1324Ile)</td>
<td align="left">5</td>
<td align="left">1 (<xref ref-type="bibr" rid="B109">Sun et al., 2018</xref>)</td>
<td align="left">0</td>
<td align="left">4 (<xref ref-type="bibr" rid="B50">Isla et al., 2004</xref>; <xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>; <xref ref-type="bibr" rid="B131">Xu et al., 2012</xref>; <xref ref-type="bibr" rid="B85">Nomura et al., 2020</xref>)</td>
</tr>
<tr>
<td align="left">Transporter</td>
<td align="left">
<italic>ABCC2(MRP2)</italic>
</td>
<td align="left">rs2273697 (G1249A, Val417Ile)</td>
<td align="left">4</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">4 (<xref ref-type="bibr" rid="B50">Isla et al., 2004</xref>; <xref ref-type="bibr" rid="B76">Ludovini et al., 2011</xref>; <xref ref-type="bibr" rid="B131">Xu et al., 2012</xref>; <xref ref-type="bibr" rid="B109">Sun et al., 2018</xref>)</td>
</tr>
<tr>
<td align="left">Transporter</td>
<td align="left">
<italic>ABCC2(MRP2)</italic>
</td>
<td align="left">rs12762549 (&#x2a;&#x2b;9383C&#x3e;G)</td>
<td align="left">2</td>
<td align="left">1 (<xref ref-type="bibr" rid="B51">Iwata et al., 2012</xref>)</td>
<td align="left">1 (<xref ref-type="bibr" rid="B34">Giovannetti et al., 2011</xref>)</td>
<td align="left">0</td>
</tr>
<tr>
<td align="left">Transporter</td>
<td align="left">
<italic>ABCC2(MRP2)</italic>
</td>
<td align="left">rs2073337 (c.1668 &#x2b; 148A&#x3e;G)</td>
<td align="left">2</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">2 (<xref ref-type="bibr" rid="B34">Giovannetti et al., 2011</xref>; <xref ref-type="bibr" rid="B76">Ludovini et al., 2011</xref>)</td>
</tr>
<tr>
<td align="left">Transporter</td>
<td align="left">
<italic>ABCB1(MDR1)</italic>
</td>
<td align="left">rs1045642(C3435T, Ile1145Ile)</td>
<td align="left">12</td>
<td align="left">1 (<xref ref-type="bibr" rid="B51">Iwata et al., 2012</xref>)</td>
<td align="left">1 (<xref ref-type="bibr" rid="B11">Cara and M Eileen, 2006</xref>)</td>
<td align="left">10 (<xref ref-type="bibr" rid="B50">Isla et al., 2004</xref>; <xref ref-type="bibr" rid="B105">Seo et al., 2009</xref>; <xref ref-type="bibr" rid="B15">Chen et al., 2010</xref>; <xref ref-type="bibr" rid="B57">Khrunin et al., 2010</xref>; <xref ref-type="bibr" rid="B34">Giovannetti et al., 2011</xref>; <xref ref-type="bibr" rid="B43">Han et al., 2011</xref>; <xref ref-type="bibr" rid="B76">Ludovini et al., 2011</xref>; <xref ref-type="bibr" rid="B131">Xu et al., 2012</xref>; <xref ref-type="bibr" rid="B104">Senk et al., 2019</xref>; <xref ref-type="bibr" rid="B117">Walia et al., 2022</xref>)</td>
</tr>
<tr>
<td align="left">Transporter</td>
<td align="left">
<italic>ABCB1(MDR1)</italic>
</td>
<td align="left">rs2032582(G2677T/A, Ala893Ser)</td>
<td align="left">7</td>
<td align="left">1 (<xref ref-type="bibr" rid="B50">Isla et al., 2004</xref>)</td>
<td align="left">0</td>
<td align="left">6 (<xref ref-type="bibr" rid="B105">Seo et al., 2009</xref>; <xref ref-type="bibr" rid="B57">Khrunin et al., 2010</xref>; <xref ref-type="bibr" rid="B76">Ludovini et al., 2011</xref>; <xref ref-type="bibr" rid="B51">Iwata et al., 2012</xref>; <xref ref-type="bibr" rid="B104">Senk et al., 2019</xref>; <xref ref-type="bibr" rid="B117">Walia et al., 2022</xref>)</td>
</tr>
<tr>
<td align="left">Transporter</td>
<td align="left">
<italic>ABCB1(MDR1)</italic>
</td>
<td align="left">rs1128503(C1236T, Gly412Gly)</td>
<td align="left">6</td>
<td align="left">2 (<xref ref-type="bibr" rid="B57">Khrunin et al., 2010</xref>; <xref ref-type="bibr" rid="B34">Giovannetti et al., 2011</xref>)</td>
<td align="left">0</td>
<td align="left">4 (<xref ref-type="bibr" rid="B50">Isla et al., 2004</xref>; <xref ref-type="bibr" rid="B76">Ludovini et al., 2011</xref>; <xref ref-type="bibr" rid="B51">Iwata et al., 2012</xref>; <xref ref-type="bibr" rid="B104">Senk et al., 2019</xref>)</td>
</tr>
<tr>
<td align="left">Transporter</td>
<td align="left">
<italic>ABCG2</italic>
</td>
<td align="left">rs2231142 (421C&#x3e;A, Gln141Lys)</td>
<td align="left">5</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">5 (<xref ref-type="bibr" rid="B50">Isla et al., 2004</xref>; <xref ref-type="bibr" rid="B81">Meyer zu Schwabedissen et al., 2005</xref>; <xref ref-type="bibr" rid="B34">Giovannetti et al., 2011</xref>; <xref ref-type="bibr" rid="B76">Ludovini et al., 2011</xref>; <xref ref-type="bibr" rid="B51">Iwata et al., 2012</xref>)</td>
</tr>
<tr>
<td align="left">Transporter</td>
<td align="left">
<italic>ABCG2</italic>
</td>
<td align="left">rs2231137 (34G&#x3e;A, Val12Met)</td>
<td align="left">3</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">3 (<xref ref-type="bibr" rid="B50">Isla et al., 2004</xref>; <xref ref-type="bibr" rid="B81">Meyer zu Schwabedissen et al., 2005</xref>; <xref ref-type="bibr" rid="B51">Iwata et al., 2012</xref>)</td>
</tr>
<tr>
<td align="left">Transporter</td>
<td align="left">
<italic>OCT2</italic>
</td>
<td align="left">rs316019 (808G/T, p.270Ala &#x3e; Ser)</td>
<td align="left">2</td>
<td align="left">0</td>
<td align="left">1 (<xref ref-type="bibr" rid="B131">Xu et al., 2012</xref>)</td>
<td align="left">1 (<xref ref-type="bibr" rid="B113">Tibaldi et al., 2008</xref>)</td>
</tr>
<tr>
<td align="left">Transporter</td>
<td align="left">
<italic>MATE1</italic>
</td>
<td align="left">rs2289669 (G/A)</td>
<td align="left">2</td>
<td align="left">1 (<xref ref-type="bibr" rid="B131">Xu et al., 2012</xref>)</td>
<td align="left">0</td>
<td align="left">1 (<xref ref-type="bibr" rid="B113">Tibaldi et al., 2008</xref>)</td>
</tr>
<tr>
<td align="left">Metabolism</td>
<td align="left">
<italic>GSTP1</italic>
</td>
<td align="left">rs1695 (A313G, Ile105Val)</td>
<td align="left">18</td>
<td align="left">2 (<xref ref-type="bibr" rid="B101">Ruzzo et al., 2014</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>)</td>
<td align="left">4 (<xref ref-type="bibr" rid="B82">Moriya et al., 2002</xref>; <xref ref-type="bibr" rid="B57">Khrunin et al., 2010</xref>; <xref ref-type="bibr" rid="B3">Bj&#xf6;rn et al., 2020b</xref>; <xref ref-type="bibr" rid="B117">Walia et al., 2022</xref>)</td>
<td align="left">12 (<xref ref-type="bibr" rid="B59">Kim et al., 2001</xref>; <xref ref-type="bibr" rid="B11">Cara and M Eileen, 2006</xref>; <xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>; <xref ref-type="bibr" rid="B34">Giovannetti et al., 2011</xref>; <xref ref-type="bibr" rid="B43">Han et al., 2011</xref>; <xref ref-type="bibr" rid="B76">Ludovini et al., 2011</xref>; <xref ref-type="bibr" rid="B51">Iwata et al., 2012</xref>; <xref ref-type="bibr" rid="B19">Cortejoso et al., 2013</xref>; <xref ref-type="bibr" rid="B104">Senk et al., 2019</xref>; <xref ref-type="bibr" rid="B70">Liblab et al., 2020</xref>; <xref ref-type="bibr" rid="B85">Nomura et al., 2020</xref>; <xref ref-type="bibr" rid="B84">Nairuz et al., 2021</xref>)</td>
</tr>
<tr>
<td align="left">Metabolism</td>
<td align="left">
<italic>GSTP1</italic>
</td>
<td align="left">rs1138272 (c.341<font color="#FE0191">&#xa0;</font>C&#x3e;T, Ala114Val)</td>
<td align="left">4</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">4 (<xref ref-type="bibr" rid="B34">Giovannetti et al., 2011</xref>; <xref ref-type="bibr" rid="B76">Ludovini et al., 2011</xref>; <xref ref-type="bibr" rid="B70">Liblab et al., 2020</xref>; <xref ref-type="bibr" rid="B84">Nairuz et al., 2021</xref>)</td>
</tr>
<tr>
<td align="left">Metabolism</td>
<td align="left">
<italic>GSTT1</italic>
</td>
<td align="left">gene deletion</td>
<td align="left">9</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">9 (<xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>; <xref ref-type="bibr" rid="B43">Han et al., 2011</xref>; <xref ref-type="bibr" rid="B51">Iwata et al., 2012</xref>; <xref ref-type="bibr" rid="B19">Cortejoso et al., 2013</xref>; <xref ref-type="bibr" rid="B104">Senk et al., 2019</xref>; <xref ref-type="bibr" rid="B70">Liblab et al., 2020</xref>; <xref ref-type="bibr" rid="B85">Nomura et al., 2020</xref>; <xref ref-type="bibr" rid="B84">Nairuz et al., 2021</xref>; <xref ref-type="bibr" rid="B117">Walia et al., 2022</xref>)</td>
</tr>
<tr>
<td align="left">Metabolism</td>
<td align="left">
<italic>GSTM1</italic>
</td>
<td align="left">gene deletion</td>
<td align="left">8</td>
<td align="left">0</td>
<td align="left">2 (<xref ref-type="bibr" rid="B70">Liblab et al., 2020</xref>; <xref ref-type="bibr" rid="B84">Nairuz et al., 2021</xref>)</td>
<td align="left">6 (<xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>; <xref ref-type="bibr" rid="B43">Han et al., 2011</xref>; <xref ref-type="bibr" rid="B51">Iwata et al., 2012</xref>; <xref ref-type="bibr" rid="B19">Cortejoso et al., 2013</xref>; <xref ref-type="bibr" rid="B85">Nomura et al., 2020</xref>; <xref ref-type="bibr" rid="B117">Walia et al., 2022</xref>)</td>
</tr>
<tr>
<td align="left">NER</td>
<td align="left">
<italic>ERCC1</italic>
</td>
<td align="left">rs11615 (C118T, Asn118Asn)</td>
<td align="left">19</td>
<td align="left">4 (<xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>; <xref ref-type="bibr" rid="B34">Giovannetti et al., 2011</xref>; <xref ref-type="bibr" rid="B43">Han et al., 2011</xref>; <xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>)</td>
<td align="left">1 (<xref ref-type="bibr" rid="B104">Senk et al., 2019</xref>)</td>
<td align="left">14 (<xref ref-type="bibr" rid="B82">Moriya et al., 2002</xref>; <xref ref-type="bibr" rid="B79">Marsh et al., 2007</xref>; <xref ref-type="bibr" rid="B105">Seo et al., 2009</xref>; <xref ref-type="bibr" rid="B15">Chen et al., 2010</xref>; <xref ref-type="bibr" rid="B76">Ludovini et al., 2011</xref>; <xref ref-type="bibr" rid="B19">Cortejoso et al., 2013</xref>; <xref ref-type="bibr" rid="B141">Zheng et al., 2014</xref>; <xref ref-type="bibr" rid="B63">Lambrechts et al., 2015</xref>; <xref ref-type="bibr" rid="B94">Qian et al., 2016</xref>; <xref ref-type="bibr" rid="B135">Yoshihama et al., 2018</xref>; <xref ref-type="bibr" rid="B70">Liblab et al., 2020</xref>; <xref ref-type="bibr" rid="B85">Nomura et al., 2020</xref>; <xref ref-type="bibr" rid="B84">Nairuz et al., 2021</xref>; <xref ref-type="bibr" rid="B117">Walia et al., 2022</xref>)</td>
</tr>
<tr>
<td align="left">NER</td>
<td align="left">
<italic>ERCC1</italic>
</td>
<td align="left">rs3212986 (C8092A)</td>
<td align="left">12</td>
<td align="left">0</td>
<td align="left">2 (<xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>; <xref ref-type="bibr" rid="B70">Liblab et al., 2020</xref>)</td>
<td align="left">10 (<xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>; <xref ref-type="bibr" rid="B43">Han et al., 2011</xref>; <xref ref-type="bibr" rid="B76">Ludovini et al., 2011</xref>; <xref ref-type="bibr" rid="B19">Cortejoso et al., 2013</xref>; <xref ref-type="bibr" rid="B141">Zheng et al., 2014</xref>; <xref ref-type="bibr" rid="B95">Qian et al., 2015</xref>; <xref ref-type="bibr" rid="B94">Qian et al., 2016</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>; <xref ref-type="bibr" rid="B84">Nairuz et al., 2021</xref>; <xref ref-type="bibr" rid="B117">Walia et al., 2022</xref>)</td>
</tr>
<tr>
<td align="left">NER</td>
<td align="left">
<italic>ERCC1</italic>
</td>
<td align="left">rs3212961(17677G&#x3e;T)</td>
<td align="left">3</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">3 (<xref ref-type="bibr" rid="B34">Giovannetti et al., 2011</xref>; <xref ref-type="bibr" rid="B76">Ludovini et al., 2011</xref>; <xref ref-type="bibr" rid="B94">Qian et al., 2016</xref>)</td>
</tr>
<tr>
<td align="left">NER</td>
<td align="left">
<italic>ERCC2/XPD</italic>
</td>
<td align="left">rs13181(A&#x3e;C, Lys751Gln)</td>
<td align="left">17</td>
<td align="left">0</td>
<td align="left">1 (<xref ref-type="bibr" rid="B15">Chen et al., 2010</xref>)</td>
<td align="left">16 (<xref ref-type="bibr" rid="B79">Marsh et al., 2007</xref>; <xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>; <xref ref-type="bibr" rid="B43">Han et al., 2011</xref>; <xref ref-type="bibr" rid="B76">Ludovini et al., 2011</xref>; <xref ref-type="bibr" rid="B141">Zheng et al., 2014</xref>; <xref ref-type="bibr" rid="B63">Lambrechts et al., 2015</xref>; <xref ref-type="bibr" rid="B62">Kumpiro et al., 2016</xref>; <xref ref-type="bibr" rid="B94">Qian et al., 2016</xref>; <xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>; <xref ref-type="bibr" rid="B135">Yoshihama et al., 2018</xref>; <xref ref-type="bibr" rid="B104">Senk et al., 2019</xref>; <xref ref-type="bibr" rid="B70">Liblab et al., 2020</xref>; <xref ref-type="bibr" rid="B85">Nomura et al., 2020</xref>; <xref ref-type="bibr" rid="B30">Ferracini et al., 2021</xref>; <xref ref-type="bibr" rid="B84">Nairuz et al., 2021</xref>; <xref ref-type="bibr" rid="B117">Walia et al., 2022</xref>)</td>
</tr>
<tr>
<td align="left">NER</td>
<td align="left">
<italic>ERCC2/XPD</italic>
</td>
<td align="left">rs1799793 (G23591A, Asp312Asn)</td>
<td align="left">13</td>
<td align="left">1 (<xref ref-type="bibr" rid="B84">Nairuz et al., 2021</xref>)</td>
<td align="left">1 (<xref ref-type="bibr" rid="B70">Liblab et al., 2020</xref>)</td>
<td align="left">11 (<xref ref-type="bibr" rid="B47">Hoffmeyer et al., 2000</xref>; <xref ref-type="bibr" rid="B79">Marsh et al., 2007</xref>; <xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>; <xref ref-type="bibr" rid="B15">Chen et al., 2010</xref>; <xref ref-type="bibr" rid="B34">Giovannetti et al., 2011</xref>; <xref ref-type="bibr" rid="B43">Han et al., 2011</xref>; <xref ref-type="bibr" rid="B141">Zheng et al., 2014</xref>; <xref ref-type="bibr" rid="B94">Qian et al., 2016</xref>; <xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>; <xref ref-type="bibr" rid="B135">Yoshihama et al., 2018</xref>; <xref ref-type="bibr" rid="B85">Nomura et al., 2020</xref>)</td>
</tr>
<tr>
<td align="left">NER</td>
<td align="left">
<italic>ERCC2/XPD</italic>
</td>
<td align="left">rs238406 (C22541A, Arg156Arg)</td>
<td align="left">5</td>
<td align="left">2 (<xref ref-type="bibr" rid="B47">Hoffmeyer et al., 2000</xref>; <xref ref-type="bibr" rid="B43">Han et al., 2011</xref>)</td>
<td align="left">0</td>
<td align="left">3 (<xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>; <xref ref-type="bibr" rid="B94">Qian et al., 2016</xref>; <xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>)</td>
</tr>
<tr>
<td align="left">NER</td>
<td align="left">
<italic>ERCC2/XPD</italic>
</td>
<td align="left">rs1052555 (G&#x3e;A, Asp711Asp)</td>
<td align="left">3</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">3 (<xref ref-type="bibr" rid="B47">Hoffmeyer et al., 2000</xref>; <xref ref-type="bibr" rid="B94">Qian et al., 2016</xref>; <xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>)</td>
</tr>
<tr>
<td align="left">NER</td>
<td align="left">
<italic>ERCC4 (XPF)</italic>
</td>
<td align="left">rs1799801(T&#x3e;C, Ser835Ser)</td>
<td align="left">2</td>
<td align="left">1 (<xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>)</td>
<td align="left">0</td>
<td align="left">1 (<xref ref-type="bibr" rid="B94">Qian et al., 2016</xref>)</td>
</tr>
<tr>
<td align="left">NER</td>
<td align="left">
<italic>XPC</italic>
</td>
<td align="left">rs2228001(A&#x3e;C, Lys939Gln)</td>
<td align="left">3</td>
<td align="left">2 (<xref ref-type="bibr" rid="B82">Moriya et al., 2002</xref>; <xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>)</td>
<td align="left">0</td>
<td align="left">1 (<xref ref-type="bibr" rid="B94">Qian et al., 2016</xref>)</td>
</tr>
<tr>
<td align="left">NER</td>
<td align="left">
<italic>XPG/ERCC5</italic>
</td>
<td align="left">rs1047768 (T&#x3e;C, His46His)</td>
<td align="left">2</td>
<td align="left">1 (<xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>)</td>
<td align="left">0</td>
<td align="left">1 (<xref ref-type="bibr" rid="B94">Qian et al., 2016</xref>)</td>
</tr>
<tr>
<td align="left">NER</td>
<td align="left">
<italic>XPG/ERCC5</italic>
</td>
<td align="left">rs17655 (G&#x3e;C, His1104Asp)</td>
<td align="left">2</td>
<td align="left">0 (<xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>)</td>
<td align="left">0</td>
<td align="left">2 (<xref ref-type="bibr" rid="B94">Qian et al., 2016</xref>)</td>
</tr>
<tr>
<td align="left">NER</td>
<td align="left">
<italic>CCNH</italic>
</td>
<td align="left">rs2230641 (A&#x3e;G, Val270Ala)</td>
<td align="left">2</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">2 (<xref ref-type="bibr" rid="B94">Qian et al., 2016</xref>; <xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>)</td>
</tr>
<tr>
<td align="left">NER</td>
<td align="left">
<italic>XPA</italic>
</td>
<td align="left">rs1800975 (T&#x3e;C)</td>
<td align="left">2</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">2 (<xref ref-type="bibr" rid="B94">Qian et al., 2016</xref>; <xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>)</td>
</tr>
<tr>
<td align="left">NER</td>
<td align="left">
<italic>RPA1</italic>
</td>
<td align="left">rs12727 (G&#x3e;C)</td>
<td align="left">2</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">2 (<xref ref-type="bibr" rid="B129">Xu et al., 1998</xref>; <xref ref-type="bibr" rid="B94">Qian et al., 2016</xref>)</td>
</tr>
<tr>
<td align="left">NER</td>
<td align="left">
<italic>RPA1</italic>
</td>
<td align="left">rs17734 (C&#x3e;T)</td>
<td align="left">2</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">2 (<xref ref-type="bibr" rid="B129">Xu et al., 1998</xref>; <xref ref-type="bibr" rid="B94">Qian et al., 2016</xref>)</td>
</tr>
<tr>
<td align="left">BER</td>
<td align="left">
<italic>XPCC1</italic>
</td>
<td align="left">rs25487 (G23885A, Arg399Gln)</td>
<td align="left">14</td>
<td align="left">3 (<xref ref-type="bibr" rid="B82">Moriya et al., 2002</xref>; <xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>; <xref ref-type="bibr" rid="B24">De Troia et al., 2019</xref>)</td>
<td align="left">2 (<xref ref-type="bibr" rid="B59">Kim et al., 2001</xref>; <xref ref-type="bibr" rid="B84">Nairuz et al., 2021</xref>)</td>
<td align="left">9 (<xref ref-type="bibr" rid="B6">Bosch et al., 2006</xref>; <xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>; <xref ref-type="bibr" rid="B76">Ludovini et al., 2011</xref>; <xref ref-type="bibr" rid="B141">Zheng et al., 2014</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>; <xref ref-type="bibr" rid="B135">Yoshihama et al., 2018</xref>; <xref ref-type="bibr" rid="B104">Senk et al., 2019</xref>; <xref ref-type="bibr" rid="B85">Nomura et al., 2020</xref>; <xref ref-type="bibr" rid="B117">Walia et al., 2022</xref>)</td>
</tr>
<tr>
<td align="left">BER</td>
<td align="left">
<italic>XPCC1</italic>
</td>
<td align="left">rs25489 (G23098A, Arg280His)</td>
<td align="left">3</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">3 (<xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>; <xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>; <xref ref-type="bibr" rid="B84">Nairuz et al., 2021</xref>)</td>
</tr>
<tr>
<td align="left">BER</td>
<td align="left">
<italic>XPCC1</italic>
</td>
<td align="left">rs1799782 (C21935T, Arg194Trp)</td>
<td align="left">4</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">4 (<xref ref-type="bibr" rid="B6">Bosch et al., 2006</xref>; <xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>; <xref ref-type="bibr" rid="B84">Nairuz et al., 2021</xref>; <xref ref-type="bibr" rid="B117">Walia et al., 2022</xref>)</td>
</tr>
<tr>
<td align="left">BER</td>
<td align="left">
<italic>APE1</italic>
</td>
<td align="left">rs1130409 (T&#x3e;G, Asp148Glu)</td>
<td align="left">2</td>
<td align="left">0</td>
<td align="left">1 (<xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>)</td>
<td align="left">1 (<xref ref-type="bibr" rid="B24">De Troia et al., 2019</xref>)</td>
</tr>
<tr>
<td align="left">BER</td>
<td align="left">
<italic>OGG1</italic>
</td>
<td align="left">rs1052133 (C&#x3e;G, Ser326Cys)</td>
<td align="left">2</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">2 (<xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>; <xref ref-type="bibr" rid="B24">De Troia et al., 2019</xref>)</td>
</tr>
<tr>
<td align="left">DSB</td>
<td align="left">
<italic>XRCC3</italic>
</td>
<td align="left">rs861539 (C&#x3e;T, Thr241Met)</td>
<td align="left">3</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">3 (<xref ref-type="bibr" rid="B63">Lambrechts et al., 2015</xref>; <xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>; <xref ref-type="bibr" rid="B85">Nomura et al., 2020</xref>)</td>
</tr>
<tr>
<td align="left">TLS</td>
<td align="left">
<italic>REV3L</italic>
</td>
<td align="left">rs462779 (G&#x3e;A, Thr1224Ile)</td>
<td align="left">2</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">2 (<xref ref-type="bibr" rid="B27">Er&#x10d;ulj et al., 2012</xref>; <xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>)</td>
</tr>
<tr>
<td align="left">TLS</td>
<td align="left">
<italic>REV3L</italic>
</td>
<td align="left">rs465646 (G&#x3e;A)</td>
<td align="left">3</td>
<td align="left">1</td>
<td align="left">0</td>
<td align="left">2 (<xref ref-type="bibr" rid="B27">Er&#x10d;ulj et al., 2012</xref>; <xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>)</td>
</tr>
<tr>
<td align="left">TLS</td>
<td align="left">
<italic>REV7</italic>
</td>
<td align="left">rs746218 (G&#x3e;A)</td>
<td align="left">2</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">2 (<xref ref-type="bibr" rid="B25">Ding-Wu et al., 2012</xref>; <xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>)</td>
</tr>
<tr>
<td align="left">TLS</td>
<td align="left">
<italic>REV7</italic>
</td>
<td align="left">rs2233006 (T&#x3e;A)</td>
<td align="left">2</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">2 (<xref ref-type="bibr" rid="B25">Ding-Wu et al., 2012</xref>; <xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>)</td>
</tr>
<tr>
<td align="left">TLS</td>
<td align="left">
<italic>REV1</italic>
</td>
<td align="left">rs3087386 (A&#x3e;G, Phe257Ser)</td>
<td align="left">2</td>
<td align="left">0</td>
<td align="left">1 (<xref ref-type="bibr" rid="B27">Er&#x10d;ulj et al., 2012</xref>)</td>
<td align="left">1 (<xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>)</td>
</tr>
<tr>
<td align="left">TLS</td>
<td align="left">
<italic>Rad18</italic>
</td>
<td align="left">rs373572 (C&#x3e;T, Arg302Gln)</td>
<td align="left">2</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">2 (<xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>; <xref ref-type="bibr" rid="B118">Wang et al., 2021</xref>)</td>
</tr>
<tr>
<td align="left">DNA synthesis</td>
<td align="left">
<italic>MTHFR</italic>
</td>
<td align="left">rs1801131 (A1298C, Glu429Ala)</td>
<td align="left">6</td>
<td align="left">0</td>
<td align="left">0</td>
<td align="left">6 (<xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>; <xref ref-type="bibr" rid="B147">Zolk et al., 2009</xref>; <xref ref-type="bibr" rid="B146">Zolk, 2012</xref>; <xref ref-type="bibr" rid="B85">Nomura et al., 2020</xref>; <xref ref-type="bibr" rid="B30">Ferracini et al., 2021</xref>; <xref ref-type="bibr" rid="B116">Walia et al., 2021</xref>)</td>
</tr>
<tr>
<td align="left">DNA synthesis</td>
<td align="left">
<italic>MTHFR</italic>
</td>
<td align="left">rs1801133 (C677T, Ala222Val)</td>
<td align="left">6</td>
<td align="left">2 (<xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>; <xref ref-type="bibr" rid="B116">Walia et al., 2021</xref>)</td>
<td align="left">1 (<xref ref-type="bibr" rid="B146">Zolk, 2012</xref>)</td>
<td align="left">3 (<xref ref-type="bibr" rid="B147">Zolk et al., 2009</xref>; <xref ref-type="bibr" rid="B85">Nomura et al., 2020</xref>; <xref ref-type="bibr" rid="B30">Ferracini et al., 2021</xref>)</td>
</tr>
<tr>
<td align="left">DNA synthesis</td>
<td align="left">
<italic>RRM1</italic>
</td>
<td align="left">rs12806698 (&#x2212;37C/A)</td>
<td align="left">2</td>
<td align="left">1 (<xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>)</td>
<td align="left">1 (<xref ref-type="bibr" rid="B15">Chen et al., 2010</xref>)</td>
<td align="left">0</td>
</tr>
<tr>
<td align="left">Apoptosis</td>
<td align="left">
<italic>MDM2</italic>
</td>
<td align="left">rs2279744 (309T&#x3e;G)</td>
<td align="left">4</td>
<td align="left">1 (<xref ref-type="bibr" rid="B83">Moyer et al., 2008</xref>)</td>
<td align="left">2 (<xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>; <xref ref-type="bibr" rid="B98">R et al., 2000</xref>)</td>
<td align="left">1 (<xref ref-type="bibr" rid="B17">Clarissa Ribeiro Reily et al., 2018</xref>)</td>
</tr>
<tr>
<td align="left">Apoptosis</td>
<td align="left">
<italic>TP53</italic>
</td>
<td align="left">rs1042522 (C&#x3e;G, Pro72Arg)</td>
<td align="left">9</td>
<td align="left">2 (<xref ref-type="bibr" rid="B84">Nairuz et al., 2021</xref>; <xref ref-type="bibr" rid="B98">R et al., 2000</xref>)</td>
<td align="left">0</td>
<td align="left">7 (<xref ref-type="bibr" rid="B83">Moyer et al., 2008</xref>; <xref ref-type="bibr" rid="B34">Giovannetti et al., 2011</xref>; <xref ref-type="bibr" rid="B76">Ludovini et al., 2011</xref>; <xref ref-type="bibr" rid="B63">Lambrechts et al., 2015</xref>; <xref ref-type="bibr" rid="B62">Kumpiro et al., 2016</xref>; <xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>; <xref ref-type="bibr" rid="B17">Clarissa Ribeiro Reily et al., 2018</xref>)</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>Abbreviations: BER, base excision repair; DSB, double-strand break repair; MMR, mismatch repair; NER, nucleotide excision repair; TLS, translesion DNA, synthesis.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="T3" position="float">
<label>TABLE 3</label>
<caption>
<p>Summary of positive associations in genetic polymorphisms that investigated more than twice.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="left">Study</th>
<th align="left">Sample size, cancer</th>
<th align="left">Treatment</th>
<th align="left">Association</th>
<th align="left">Trend</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td colspan="5" align="left">
<italic>ABCC2(MRP2)</italic> rs717620 (C-24T)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B65">Lee et al. (2013)</xref>
</td>
<td align="left">292 Colon cancer</td>
<td align="left">L-OHP &#x2b; LV &#x2b; 5-FU</td>
<td align="left">Lower incident rate of grade 3-4 thrombocytopenia [5.6% (9 out of 160 patients with CC) vs. 0.8% (1 out of 124 with CT or TT), <italic>p</italic> &#x3d; 0.047]</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>ABCC2(MRP2)</italic> rs3740066 (C3972T, Ile1324Ile)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B43">Han et al. (2011)</xref>
</td>
<td align="left">445 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOther DDP/CBP combinations</td>
<td align="left">Increased risk of grade 3-4 thrombocytopenia (CT &#x2b; TT vs. CC OR &#x3d; 2.43; 95% CI: 1.06&#x2013;5.56; <italic>p</italic> &#x3d; 0.034)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>ABCC2(MRP2)</italic> rs12762549 (&#x2a;&#x2b;9383C&#x3e;G)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B85">Nomura et al. (2020)</xref>
</td>
<td align="left">158 Esophageal cancer</td>
<td align="left">DDP &#x2b; TXT &#x2b; 5-FU</td>
<td align="left">Increased risk of grade 3-4 neutropenia (GG vs. GC &#x2b; CC OR &#x3d; 2.342; 95% CI: 1.108&#x2013;4.948; <italic>p</italic> &#x3d; 0.026)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B63">Lambrechts et al. (2015)</xref>
</td>
<td align="left">290 Ovarian cancer</td>
<td align="left">CBP &#x2b; PTX<break/>CBP mono-therapy</td>
<td align="left">Decreased risk of grade 3-4 anemia in additive model (OR &#x3d; 0.51; 95% CI: 0.33&#x2013;0.81; <italic>p</italic> &#x3d; 0.004)</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>ABCB1(MDR1)</italic> rs1045642(C3435T, Ile1145Ile)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B85">Nomura et al. (2020)</xref>
</td>
<td align="left">158 Esophageal cancer</td>
<td align="left">DDP &#x2b; TXT &#x2b; 5-FU</td>
<td align="left">Increased risk of grade 3-4 neutropenia (CT &#x2b; TT vs. CC OR &#x3d; 2.191; 95% CI: 1.087&#x2013;4.417; <italic>p</italic> &#x3d; 0.028)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B24">De Troia et al. (2019)</xref>
</td>
<td align="left">82 Lung cancer</td>
<td align="left">DDP/CBP &#x2b; VP-16/NVBDDP &#x2b; GEM/PEM/TXT<break/>DDP monotherapy</td>
<td align="left">Decreased risk of grade 3-4 hematological toxicity (CT vs. CC OR &#x3d; 0.18; 95% CI: 0.05&#x2013;0.65; <italic>p</italic> &#x3d; 0.01, CT &#x2b; TT vs. CC OR &#x3d; 0.24; 95% CI: 0.07&#x2013;0.75; <italic>p</italic> &#x3d; 0.01)</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>ABCB1(MDR1)</italic> rs2032582(G2677T/A, Ala893Ser)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B44">Han et al. (2007)</xref>
</td>
<td align="left">107 NSCLC</td>
<td align="left">DDP &#x2b; CPT-11</td>
<td align="left">Associated with grade 4 neutropenia (the incident rate of grade 4 neutropenia for GG, GT/GA and TT/TA/AA were 34.6%, 53.8%, and 11.5%, <italic>p</italic> &#x3d; 0.030)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>ABCB1(MDR1)</italic> rs1128503(C1236T, Gly412Gly)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B63">Lambrechts et al. (2015)</xref>
</td>
<td align="left">290 Ovarian cancer</td>
<td align="left">CBP &#x2b; PTX<break/>CBP mono-therapy</td>
<td align="left">Increased risk of grade 3-4 anemia in additive model (OR &#x3d; 1.71; 95% CI: 1.07&#x2013;2.71; <italic>p</italic> &#x3d; 0.023)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B30">Ferracini et al. (2021)</xref>
</td>
<td align="left">112 Ovarian cancer (Epithelial ovarian cancer)</td>
<td align="left">CBP &#x2b; PTX<break/>CBP mono-therapy</td>
<td align="left">Increased risk of grade 1-4 thrombocytopenia (TT vs. CC OR &#x3d; 3.63; 95% CI: 0.98&#x2013;13.47; <italic>p</italic> &#x3d; 0.05, TT vs. CT &#x2b; CC OR &#x3d; 3.50; 95% CI: 1.12&#x2013;10.97; <italic>p</italic> &#x3d; 0.03)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>OCT2</italic> rs316019 (808G/T, p.270Ala &#x3e; Ser)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B94">Qian et al. (2016)</xref>
</td>
<td align="left">403 NSCLC</td>
<td align="left">DDP/CBP &#x2b; GEM/PEM/PTX/TXT/NVB</td>
<td align="left">Decreased risk of grade 3-4 hematological toxicity in additive model (OR &#x3d; 0.58; 95% CI: 0.34&#x2013;0.97; <italic>p</italic> &#x3d; 0.039)</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>MATE1</italic> rs2289669 (G/A)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B94">Qian et al. (2016)</xref>
</td>
<td align="left">403 NSCLC</td>
<td align="left">DDP/CBP &#x2b; GEM/PEM/PTX/TXT/NVB</td>
<td align="left">Increased risk of grade 3-4 hematological toxicity in recessive model (OR &#x3d; 1.92; 95% CI: 1.13&#x2013;3.25; <italic>p</italic> &#x3d; 0.016)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>GSTP1</italic> rs1695 (A313G, Ile105Val)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B30">Ferracini et al. (2021)</xref>
</td>
<td align="left">112 Ovarian cancer (Epithelial ovarian cancer)</td>
<td align="left">CBP &#x2b; PTX<break/>CBP mono-therapy</td>
<td align="left">Decreased risk of grade 3-4 anemia (AG vs. AA OR &#x3d; 0.16; 95% CI: 0.03&#x2013;0.84; <italic>p</italic> &#x3d; 0.03, AG &#x2b; GG vs. AA OR &#x3d; 0.17; 95% CI: 0.04&#x2013;0.69; <italic>p</italic> &#x3d; 0.01), grade 3-4 thrombocytopenia (AG vs. AA OR &#x3d; 0.32; 95% CI: 0.12&#x2013;0.82; <italic>p</italic> &#x3d; 0.01, GG vs. AA OR &#x3d; 0.11; 95% CI: 0.02&#x2013;0.59; <italic>p</italic> &#x3c; 0.01, AG &#x2b; GG vs. AA OR &#x3d; 0.27; 95% CI: 0.12&#x2013;0.64; <italic>p</italic> &#x3c; 0.01, GG vs. AA&#x2b; AG OR &#x3d; 0.18; 95% CI: 0.03&#x2013;0.85; <italic>p</italic> &#x3d; 0.03)</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B58">Kim et al. (2009)</xref>
</td>
<td align="left">118 Ovarian cancer (Epithelial ovarian cancer)</td>
<td align="left">DDP/CBP &#x2b; PTX<break/>CBP &#x2b; TXT</td>
<td align="left">Associated with grade 3-4 hematological toxicity (the incident rate of grade 3-4 hematology toxicity for AG/GG and AA were 54.2% and 78.7%, <italic>p</italic> &#x3d; 0.015)</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B7">Bushra et al. (2020)</xref>
</td>
<td align="left">285 NSCLC</td>
<td align="left">DDP/CBP &#x2b; GEM/NVB/PTX/TXT</td>
<td align="left">Decreased risk of grade 3-4 anemia (GG vs. AA OR &#x3d; 0.29; 95% CI: 0.10&#x2013;0.87; <italic>p</italic> &#x3d; 0.027) and grade 3-4 neutropenia (GG vs. AA OR &#x3d; 0.31; 95% CI: 0.10&#x2013;0.96; <italic>p</italic> &#x3d; 0.043)</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B135">Yoshihama et al. (2018)</xref>
</td>
<td align="left">320 Ovarian fallopian tube, peritoneal, uterine, or cervical cancer</td>
<td align="left">CBP &#x2b; PTX</td>
<td align="left">Decreased risk of severe hematotoxicity (including neutropenia G4, thrombocytopenia &#x2265; G3,and anemia &#x2265; G3) (A allele vs. G allele OR &#x3d; 5.71; 95% CI: 1.77&#x2013;18.44; <italic>p</italic> &#x3d; 0.00034)</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B116">Walia et al. (2021)</xref>
</td>
<td align="left">317 Lung cancer</td>
<td align="left">DDP/CBP &#x2b; PEM/CPT-11/TXT/PTX/GEM</td>
<td align="left">Increased risk of grade 3-4 anemia (AG vs. AA OR &#x3d; 2.12; 95% CI: 0.97&#x2013;4.62; <italic>p</italic> &#x3d; 0.04) and grade 2-4 leukopenia (GG vs. AA OR &#x3d; 2.41; 95% CI: 1.39&#x2013;4.18; <italic>p</italic> &#x3d; 0.001)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B70">Liblab et al. (2020)</xref>
</td>
<td align="left">52 Ovarian cancer (Epithelial ovarian cancer)</td>
<td align="left">CBP &#x2b; PTX<break/>CBP mono-therapy</td>
<td align="left">Higher incident rate of grade 2-4 anemia [46.34% (AA) vs. 81.82% (AG), <italic>p</italic> &#x3d; 0.036]</td>
<td align="left">Increase</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>GSTM1</italic> gene deletion</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B27">Er&#x10d;ulj et al. (2012)</xref>
</td>
<td align="left">94 Malignant mesothelioma</td>
<td align="left">DDP/CBP &#x2b; GEM/PEM<break/>DDP &#x2b; MMC &#x2b; VCR</td>
<td align="left">Decreased risk of grade 2-4 leukopenia (0/0 vs. 1/1 &#x2b; 1/0 OR &#x3d; 0.43; 95% CI: 0.18&#x2013;0.99; <italic>p</italic> &#x3d; 0.048)</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B57">Khrunin et al. (2010)</xref>
</td>
<td align="left">104 Ovarian cancer</td>
<td align="left">DDP &#x2b; CTX</td>
<td align="left">Decreased risk of grade 1-4 thrombocytopenia (0/0 vs. 1/0 OR &#x3d; 0.13; 95% CI: 0.03&#x2013;0.62; <italic>p</italic> &#x3d; 0.005), grade 2-4 anemia (0/0 vs. 1/0 OR &#x3d; 0.29; 95% CI: 0.13&#x2013;0.66; <italic>p</italic> &#x3d; 0.003)</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>ERCC1</italic> rs11615 (C118T, Asn118Asn)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B65">Lee et al. (2013)</xref>
</td>
<td align="left">292 Colon cancer</td>
<td align="left">L-OHP &#x2b; LV &#x2b; 5-FU</td>
<td align="left">Increased risk of grade 3-4 neutropenia (TT vs. TC &#x2b; CC OR &#x3d; 4.58, 95% CI: 1.20&#x2013;17.40, <italic>p</italic> &#x3d; 0.026)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B64">Lavanderos et al. (2019)</xref>
</td>
<td align="left">119 Testicular cancer</td>
<td align="left">DDP &#x2b; BLM &#x2b; VP-16</td>
<td align="left">Increased risk of grade 3-4 febrile neutropenia (TT vs. CC &#x2b; CT OR &#x3d; 4.89; 95% CI: 1.06&#x2013;22.56; <italic>p</italic> &#x3d; 0.042)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B63">Lambrechts et al. (2015)</xref>
</td>
<td align="left">290 Ovarian cancer</td>
<td align="left">CBP &#x2b; PTX<break/>CBP mono-therapy</td>
<td align="left">Increased risk of grade 3-4 anemia in additive model (OR &#x3d; 1.61; 95% CI: 1.04&#x2013;2.50; <italic>p</italic> &#x3d; 0.031)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B144">Zheng et al. (2017)</xref>
</td>
<td align="left">437 in the in a discovery cohort and 781 in the validation cohort NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXT/PEM</td>
<td align="left">Increased risk of grade 3-4 anemia in dominant model in discovery cohort (OR &#x3d; 2.230; 95% CI: 1.041&#x2013;4.775; <italic>p</italic> &#x3d; 0.039)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B19">Cortejoso et al. (2013)</xref>
</td>
<td align="left">106 Colorectal cancer</td>
<td align="left">L-OHP &#x2b; 5-FU &#x2b; LV<break/>L-OHP &#x2b; CAP</td>
<td align="left">Decreased risk of grade 3-4 neutropenia (CT &#x2b; TT vs. CC OR &#x3d; 0.205; 95% CI: 0.061&#x2013;0.690; <italic>p</italic> &#x3d; 0.010)</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>ERCC1</italic> rs3212986 (C8092A)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B144">Zheng et al. (2017)</xref>
</td>
<td align="left">437 in the in a discovery cohort and 781 in the validation cohort NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXT/PEM</td>
<td align="left">Decreased risk of grade 3-4 hematologic toxicity in recessive model in discovery cohort (OR &#x3d; 0.326; 95% CI: 0.123&#x2013;0.861; <italic>p</italic> &#x3d; 0.024)</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B27">Er&#x10d;ulj et al. (2012)</xref>
</td>
<td align="left">94 Malignant mesothelioma</td>
<td align="left">DDP/CBP &#x2b; GEM/PEM<break/>DDP &#x2b; MMC &#x2b; VCR</td>
<td align="left">Decreased risk of grade 2-4 leukopenia (CA &#x2b; AA vs. CC OR &#x3d; 0.18; 95% CI: 0.04&#x2013;0.86; <italic>p</italic> &#x3d; 0.032)</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>ERCC2/XPD</italic> rs13181(A&#x3e;C, Lys751Gln)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B50">Isla et al. (2004)</xref>
</td>
<td align="left">62 NSCLC</td>
<td align="left">DDP &#x2b; TXT</td>
<td align="left">Associated with grade 2-4 neutropenia (the incident rate of grade 2-4 neutropenia for Lys/Lys, Lys/Gln and Gln/Gln were 48%, 19%, and 14%, <italic>p</italic> &#x3d; 0.04)</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>ERCC2/XPD</italic> rs1799793 (G23591A, Asp312Asn)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B27">Er&#x10d;ulj et al. (2012)</xref>
</td>
<td align="left">94 Malignant mesothelioma</td>
<td align="left">DDP/CBP &#x2b; GEM/PEM<break/>DDP &#x2b; MMC &#x2b; VCR</td>
<td align="left">Decreased risk of grade 1-4 thrombocytopenia (Asp/Asn &#x2b; Asn/Asn vs. Asp/Asp OR &#x3d; 0.15; 95% CI: 0.04&#x2013;0.61; <italic>p</italic> &#x3d; 0.008)</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B57">Khrunin et al. (2010)</xref>
</td>
<td align="left">104 Ovarian cancer</td>
<td align="left">DDP &#x2b; CTX</td>
<td align="left">Associated with grade 1-4 thrombocytopenia (Asp/Asn vs. Asp/Asp &#x2b; Asn/Asn OR &#x3d; 4.05; 95% CI: 1.21&#x2013;13.58; <italic>p</italic> &#x3d; 0.027), grade 2-4 anemia (Asp/Asn vs. Asp/Asp &#x2b; Asn/Asn OR &#x3d; 2.32; 95% CI: 1.05&#x2013;5.13; <italic>p</italic> &#x3d; 0.048)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>ERCC2/XPD</italic> rs238406 (C22541A, Arg156Arg)</td>
</tr>
<tr>
<td align="left">(<xref ref-type="bibr" rid="B128">Wu et al. 2009</xref>)</td>
<td align="left">209 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOthers DDP/CBP combinations</td>
<td align="left">Increased risk of grade 3-4 hematologic toxicity (AA vs. CC OR &#x3d; 3.24; 95% CI: 1.35&#x2013;7.78; <italic>p</italic> &#x3d; 0.009), grade 3-4 leukopenia toxicity (AA vs. CC OR &#x3d; 4.88; 95% CI: 1.67&#x2013;14.26; <italic>p</italic> &#x3d; 0.005)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B64">Lavanderos et al. (2019)</xref>
</td>
<td align="left">119 Testicular cancer</td>
<td align="left">DDP &#x2b; BLM &#x2b; VP-16</td>
<td align="left">Increased risk of grade 3-4 leukopenia (CA &#x2b; AA vs. CC OR &#x3d; 4.09; 95% CI: 1.04&#x2013;15.99; <italic>p</italic> &#x3d; 0.043)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>ERCC4 (XPF)</italic> rs1799801(T&#x3e;C, Ser835Ser)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B144">Zheng et al. (2017)</xref>
</td>
<td align="left">437 in the in a discovery cohort and 781 in the validation cohort NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXT/PEM</td>
<td align="left">Increased risk of grade 3-4 hematologic toxicity in additive model (OR &#x3d; 1.555; 95% CI: 1.041&#x2013;2.323; <italic>p</italic> &#x3d; 0.031) and grade 3-4 thrombocytopenia in dominant model (OR &#x3d; 3.562; 95% CI: 1.513&#x2013;8.390; <italic>p</italic> &#x3d; 0.004) in discovery cohort</td>
<td align="left">Increase</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>XPC</italic> rs2228001(A&#x3e;C, Lys939Gln)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B7">Bushra et al. (2020)</xref>
</td>
<td align="left">285 NSCLC</td>
<td align="left">DDP/CBP &#x2b; GEM/NVB/PTX/TXT</td>
<td align="left">Decreased risk of grade 3-4 anemia (CC vs. AA OR &#x3d; 0.18; 95% CI: 0.04&#x2013;0.82; <italic>p</italic> &#x3d; 0.027) and Increased risk of grade 3-4 neutropenia (AC vs. AA OR &#x3d; 3.31; 95% CI: 1.74&#x2013;6.31; <italic>p</italic> &#x3d; 0.0003, AC &#x2b; CC vs. AA OR &#x3d; 2.63; 95% CI: 1.41&#x2013;4.90; <italic>p</italic> &#x3d; 0.002)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B144">Zheng et al. (2017)</xref>
</td>
<td align="left">437 in the in a discovery cohort and 781 in the validation cohort NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXT/PEM</td>
<td align="left">Increased risk of grade 3-4 leukocytopenia in dominant model in discovery cohort (OR &#x3d; 2.217; 95% CI: 1.054&#x2013;4.665; <italic>p</italic> &#x3d; 0.036)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>XPG/ERCC5</italic> rs1047768 (T&#x3e;C, His46His)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B144">Zheng et al. (2017)</xref>
</td>
<td align="left">437 in the in a discovery cohort and 781 in the validation cohort NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXT/PEM</td>
<td align="left">Increased risk of grade 3-4 leukocytopenia in additive model in discovery cohort (OR &#x3d; 1.701; 95% CI: 1.021&#x2013;2.835; <italic>p</italic> &#x3d; 0.041)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>XPG/ERCC5</italic> rs17655 (G&#x3e;C, His1104Asp)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B144">Zheng et al. (2017)</xref>
</td>
<td align="left">437 in the in a discovery cohort and 781 in the validation cohort NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXT/PEM</td>
<td align="left">Increased risk of grade 3-4 thrombocytopenia in additive model in discovery cohort (OR &#x3d; 2.165; 95% CI: 1.191&#x2013;3.938; <italic>p</italic> &#x3d; 0.011)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>XPCC1</italic> rs25487 (G23885A, Arg399Gln)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B7">Bushra et al. (2020)</xref>
</td>
<td align="left">285 NSCLC</td>
<td align="left">DDP/CBP &#x2b; GEM/NVB/PTX/TXT</td>
<td align="left">Increased risk of grade 3-4 anemia (AA&#x2b; AG vs. GG OR &#x3d; 2.0; 95% CI: 1.19&#x2013;3.35; <italic>p</italic> &#x3d; 0.008, AG vs. GG OR &#x3d; 2.27; 95% CI: 1.32&#x2013;3.91; <italic>p</italic> &#x3d; 0.003), grade 3-4 neutropenia (AG vs. GG OR &#x3d; 2.37; 95% CI: 1.37&#x2013;4.07; <italic>p</italic> &#x3d; 0.002, AA&#x2b; AG vs. GG OR &#x3d; 1.98; 95% CI: 1.18&#x2013;3.33; <italic>p</italic> &#x3d; 0.010), grade 3-4 leukopenia (AG vs. GG OR &#x3d; 1.79; 95% CI: 1.0&#x2013;3.18; <italic>p</italic> &#x3d; 0.049) and grade 3-4 thrombocytopenia (AG vs. GG OR &#x3d; 2.14; 95% CI: 1.09&#x2013;4.20; <italic>p</italic> &#x3d; 0.027, AA&#x2b; AG vs. GG OR &#x3d; 2.11; 95% CI: 1.10&#x2013;4.06; <italic>p</italic> &#x3d; 0.025)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B92">Peng et al. (2014)</xref>
</td>
<td align="left">235 NSCLC</td>
<td align="left">DDP &#x2b; PTX/GEM/NVB/PEM</td>
<td align="left">Increased risk of grade 3-4 hematologic toxicity (AG vs. GG OR &#x3d; 1.929; 95% CI: 1.069-3.481<font color="#FE0191">&#xa0;</font>
<italic>p</italic> &#x3d; 0.029, AA vs. GG OR &#x3d; 4.885; 95% CI: 1.147&#x2013;20.197; <italic>p</italic> &#x3d; 0.032, AG &#x2b; AA vs. GG OR &#x3d; 2.135; 95% CI: 1.207&#x2013;3.777; <italic>p</italic> &#x3d; 0.009)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B144">Zheng et al. (2017)</xref>
</td>
<td align="left">437 in the in a discovery cohort and 781 in the validation cohort NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXT/PEM</td>
<td align="left">Increased risk of grade 3-4 leukocytopenia in recessive model (OR &#x3d; 2.841; 95% CI: 1.051&#x2013;7.681; <italic>p</italic> &#x3d; 0.040) and grade 3-4 thrombocytopenia in additive model (OR &#x3d; 2.033; 95% CI: 1.113&#x2013;3.715; <italic>p</italic> &#x3d; 0.021) in discovery cohort</td>
<td align="left">Increase</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B23">Deng et al. (2015)</xref>
</td>
<td align="left">97 NSCLC</td>
<td align="left">DDP &#x2b; GEM/NVB/PTX/TXT</td>
<td align="left">Decreased risk of grade 1-4 lymphopenia (AG &#x2b; AA vs. GG OR &#x3d; 0.323; 95% CI: 0.121&#x2013;0.862; <italic>p</italic> &#x3d; 0.024)</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B57">Khrunin et al. (2010)</xref>
</td>
<td align="left">104 Ovarian cancer</td>
<td align="left">DDP &#x2b; CTX</td>
<td align="left">Decreased risk of grade 3-4 neutropenia (GG vs. AG &#x2b; AA OR &#x3d; 3.02; 95% CI: 1.33&#x2013;6.88; <italic>p</italic> &#x3d; 0.009)</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>APE1</italic> rs1130409 (T&#x3e;G, Asp148Glu)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B144">Zheng et al. (2017)</xref>
</td>
<td align="left">437 in the in a discovery cohort and 781 in the validation cohort NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXT/PEM</td>
<td align="left">Decreased risk of grade 3-4 leukocytopenia in dominant model (OR &#x3d; 0.460; 95% CI: 0.241&#x2013;0.879; <italic>p</italic> &#x3d; 0.019), grade 3-4 neutropenia in dominant model (OR &#x3d; 0.557; 95% CI: 0.321&#x2013;0.967; <italic>p</italic> &#x3d; 0.038) in discovery cohort</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>REV3</italic> rs465646 (G&#x3e;A)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B132">Ye et al. (2015)</xref>
</td>
<td align="left">663 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOthers DDP/CBP combinations</td>
<td align="left">Increased risk of grade 3-4 hematologic toxicity (A/G &#x2b; A/A vs. G/G OR &#x3d; 2.54; 95% CI: 1.17&#x2013;5.42; <italic>p</italic> &#x3d; 0.016)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>REV1</italic> rs3087386 (A&#x3e;G, Phe257Ser)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B39">Gori&#x10d;ar et al. (2014)</xref>
</td>
<td align="left">139 Malignant mesothelioma</td>
<td align="left">DDP &#x2b; GEM/PEM<break/>Other DDP doublets</td>
<td align="left">Decreased risk of grade 2-4 neutropenia (GA &#x2b; AA vs. GG OR &#x3d; 0.38; 95% CI: 0.17&#x2013;0.84; <italic>p</italic> &#x3d; 0.017)</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>MTHFR</italic> rs1801133 (C677T, Ala222Val)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B117">Walia et al. (2022)</xref>
</td>
<td align="left">123 Lung adenocarcinoma cancer</td>
<td align="left">DDP/CBP &#x2b; PEM</td>
<td align="left">Increased risk of grade 1-3 neutropenia (CT vs. CC OR &#x3d; 5.34; 95% CI: 1.49&#x2013;19.06; <italic>p</italic> &#x3d; 0.009, CT &#x2b; TT vs. CC OR &#x3d; 4.45; 95% CI: 1.28&#x2013;15.43; <italic>p</italic> &#x3d; 0.019)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B65">Lee et al. (2013)</xref>
</td>
<td align="left">292 Colon cancer</td>
<td align="left">L-OHP &#x2b; LV &#x2b; 5-FU</td>
<td align="left">Increased risk of grade 3-4 neutropenia (TT vs. CC &#x2b; CT OR &#x3d; 2.32, 95% CI: 1.19&#x2013;4.55, <italic>p</italic> &#x3d; 0.014)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B68">Li et al. (2014)</xref>
</td>
<td align="left">1004 NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXTOther DDP/CBP combinations</td>
<td align="left">Decreased risk of grade 3-4 thrombocytopenia (CT vs. CC OR &#x3d; 0.40; 95% CI: 0.19&#x2013;0.85; <italic>p</italic> &#x3d; 0.016)</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>RRM1</italic> rs12806698(-37C/A)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B50">Isla et al. (2004)</xref>
</td>
<td align="left">62 NSCLC</td>
<td align="left">DDP &#x2b; TXT</td>
<td align="left">Associated with grade 2-4 leukopenia (the incident rate of grade 2-4 leukopenia for CC and CA were 31% and 10%, <italic>p</italic> &#x3d; 0.05)</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B144">Zheng et al. (2017)</xref>
</td>
<td align="left">437 in the in a discovery cohort and 781 in the validation cohort NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXT/PEM</td>
<td align="left">Increased risk of grade 3-4 leukocytopenia in recessive model (OR &#x3d; 5.095; 95% CI: 2.132&#x2013;12.170; <italic>p</italic> &#x3d; 0.0002), grade 3-4 neutropenia in recessive model (OR &#x3d; 2.561; 95% CI: 1.075&#x2013;6.099; <italic>p</italic> &#x3d; 0.034) in discovery cohort</td>
<td align="left">Increase</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>MDM2</italic> rs2279744 (309T&#x3e;G)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B144">Zheng et al. (2017)</xref>
</td>
<td align="left">437 in the in a discovery cohort and 781 in the validation cohort NSCLC</td>
<td align="left">DDP/CBP &#x2b; NVB/GEM/PTX/TXT/PEM</td>
<td align="left">Decreased risk of grade 3-4 thrombocytopenia in additive model (OR &#x3d; 0.472; 95% CI: 0.257&#x2013;0.866; <italic>p</italic> &#x3d; 0.015) in discovery cohort</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B120">Wang et al. (2014)</xref>
</td>
<td align="left">119 SCLC</td>
<td align="left">DDP &#x2b; VP-16</td>
<td align="left">Decreased risk of grade 3-4 neutropenia in additive model (OR &#x3d; 0.48; 95% CI: 0.2652&#x2013;0.8709; <italic>p</italic> &#x3d; 0.015) and in recessive model (OR &#x3d; 0.27; 95% CI: 0.08763&#x2013;0.8859; <italic>p</italic> &#x3d; 0.030)</td>
<td align="left">Decrease</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B42">Guo et al. (2016)</xref>
</td>
<td align="left">292 Lung adenocarcinoma</td>
<td align="left">DDP/CBP combinations</td>
<td align="left">Increased risk of grade 3-4 hematologic toxicity in recessive model (OR &#x3d; 2.128; 95% CI: 1.198&#x2013;3.777; <italic>p</italic> &#x3d; 0.010)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td colspan="5" align="left">
<italic>TP53</italic> rs1042522 (C&#x3e;G, Pro72Arg)</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B57">Khrunin et al. (2010)</xref>
</td>
<td align="left">104 Ovarian cancer</td>
<td align="left">DDP &#x2b; CTX</td>
<td align="left">Increased risk of grade 3-4 neutropenia (GG vs. CC &#x2b; CG OR &#x3d; 8.57; 95% CI: 1.05&#x2013;69.8; <italic>p</italic> &#x3d; 0.023)</td>
<td align="left">Increase</td>
</tr>
<tr>
<td align="left">
<xref ref-type="bibr" rid="B120">Wang et al. (2014)</xref>
</td>
<td align="left">119 SCLC</td>
<td align="left">DDP &#x2b; VP-16</td>
<td align="left">Increased risk of grade 3-4 neutropenia in recessive model (OR &#x3d; 3.44; 95% CI: 1.302&#x2013;9.111; <italic>p</italic> &#x3d; 0.012)</td>
<td align="left">Increase</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>Abbreviations: BLM, bleomycin; CAP, capecitabine; CBP, carboplatin; CI, confidence interval; CPT-11, irinotecan; CTX, cyclophosphamide; DDP, cisplatin; GEM, gemcitabine; L-OHP, oxaliplatin; LV, leucovorin; MMC, mitomycin C; NSCLC, non-small cell lung cancer; NVB, navelbine; OR, odds ratios; PEM, pemetrexed; PTX, paclitaxel; SCLC, small cell lung cancer; TXT, docetaxel; VCR, vincristine; VP-16, etoposide; 5-FU, fluorouracil.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<sec id="s3-3-1">
<title>3.3.1 Transportation for influx</title>
<sec id="s3-3-1-1">
<title>3.3.1.1 SLC31A1 (CTR1)</title>
<p>The main route of platinum agents entering the cell is through the copper transporter CTR1 (SLC31A1) (<xref ref-type="bibr" rid="B35">Giuliano, 2012</xref>). Because of the lack of candidate SNPs, studies were limited. <italic>SLC31A1(CTR1)</italic> rs10981699 (<xref ref-type="bibr" rid="B131">Xu et al., 2012</xref>; <xref ref-type="bibr" rid="B109">Sun et al., 2018</xref>), rs10817465 (<xref ref-type="bibr" rid="B131">Xu et al., 2012</xref>; <xref ref-type="bibr" rid="B109">Sun et al., 2018</xref>), rs12686377 (<xref ref-type="bibr" rid="B131">Xu et al., 2012</xref>; <xref ref-type="bibr" rid="B62">Kumpiro et al., 2016</xref>) were analyzed in two studies respectively. No association has been found.</p>
</sec>
</sec>
<sec id="s3-3-2">
<title>3.3.2 Transportation for efflux</title>
<sec id="s3-3-2-1">
<title>3.3.2.1 ABCC2 (MRP2)</title>
<p>The multi-drug resistance protein (MRP2), encoded for by <italic>ABCC2</italic>, involved in pumping cisplatin out of the cell (<xref ref-type="bibr" rid="B11">Cara and M Eileen, 2006</xref>). The frequently investigated genetic polymorphisms in <italic>ABCC2</italic> were rs717620 (C-24T) (n &#x3d; 6), rs3740066 (C3972T, Ile1324Ile) (n &#x3d; 5), rs2273697 (G1249A) (n &#x3d; 4), rs12762549(&#x2a;&#x2b;9383C&#x3e;G) (n &#x3d; 2), and rs2073337 (c.1668 &#x2b; 148A&#x3e;G) (n &#x3d; 2). <italic>ABCC2</italic> rs717620 (C-24&#xa0;T) and <italic>ABCC2</italic> rs3740066 (C3972T, Ile1324Ile) may not affect the expression of MRP2 mRNA or protein (<xref ref-type="bibr" rid="B82">Moriya et al., 2002</xref>; <xref ref-type="bibr" rid="B81">Meyer zu Schwabedissen et al., 2005</xref>), while <italic>ABCC2</italic> rs2273697 (G1249A) resulted in a significantly reduced expression of mRNA in human preterm placenta (<xref ref-type="bibr" rid="B81">Meyer zu Schwabedissen et al., 2005</xref>).</p>
<p>Positive association were reported in only few studies. <italic>ABCC2</italic> rs717620 (C-24T) CC genotype present increased rate of grade 3-4 thrombocytopenia in contrast to CT and TT genotypes in 292 colon cancer patients treated with FOLFOX chemotherapy (5.6% vs. 0.8%, <italic>p</italic> &#x3d; 0.047) (<xref ref-type="bibr" rid="B65">Lee et al., 2013</xref>). <italic>ABCC2</italic> rs3740066(C3972T, Ile1324Ile) T allele was suggested as a risk factor for grade 3-4 thrombocytopenia in 445 NSCLC patients receiving platinum-based chemotherapy (OR &#x3d; 2.43; 95% CI: 1.06&#x2013;5.56; <italic>p</italic> &#x3d; 0.034) (<xref ref-type="bibr" rid="B43">Han et al., 2011</xref>). As for <italic>ABCC2</italic> rs12762549(G1249A), two studies show inconsistent results. Nomura et al. found a higher risk of grade 3-4 neutropenia in GG genotype in 158 esophageal cancer patients treated with docetaxel, cisplatin, and 5-fluorouracil chemotherapy (OR &#x3d; 2.342; 95% CI: 1.108&#x2013;4.948; <italic>p</italic> &#x3d; 0.026) (<xref ref-type="bibr" rid="B85">Nomura et al., 2020</xref>). In contrast, <italic>ABCC2</italic> rs12762549 is associated with decreased risk of grade 3-4 anemia in additive model (OR &#x3d; 0.51; 95% CI: 0.33&#x2013;0.81; <italic>p</italic> &#x3d; 0.004) among 290 ovarian cancer patients upon treatment with paclitaxel and carboplatin (<xref ref-type="bibr" rid="B63">Lambrechts et al., 2015</xref>). No association has been found with the <italic>ABCC2</italic> rs2073337 (<xref ref-type="bibr" rid="B79">Marsh et al., 2007</xref>; <xref ref-type="bibr" rid="B63">Lambrechts et al., 2015</xref>) and rs2273697 (<xref ref-type="bibr" rid="B44">Han et al., 2007</xref>; <xref ref-type="bibr" rid="B79">Marsh et al., 2007</xref>; <xref ref-type="bibr" rid="B43">Han et al., 2011</xref>; <xref ref-type="bibr" rid="B94">Qian et al., 2016</xref>).</p>
</sec>
<sec id="s3-3-2-2">
<title>3.3.2.2 ABCB1 (MDR1)</title>
<p>ABCB1 (MDR1 or p-glycoprotein) is thought to play a role in platinum efflux, although to a much lesser extent than the copper transporters or MRP2 (<xref ref-type="bibr" rid="B11">Cara and M Eileen, 2006</xref>). As to <italic>ABCB1</italic> rs1045642(C3435T), the homozygous T-allele is associated with significantly lower duodenal MDR-1 expression and the highest digoxin plasma levels (<xref ref-type="bibr" rid="B47">Hoffmeyer et al., 2000</xref>). 12 studies were available for <italic>ABCB1</italic> rs1045642(C3435T) but the results have not been consistent. De Troia B et al. reported that patients carrying 3435T allele had a lower risk of grade 3-4 neutropenia in 82 lung cancer patients treated with platinum-based chemotherapy (OR &#x3d; 0.24; 95% CI: 0.07&#x2013;0.75; <italic>p</italic> &#x3d; 0.01) (<xref ref-type="bibr" rid="B24">De Troia et al., 2019</xref>). In contrast to these results, Nomura, H. et al. found T allele carriers were more likely to develop grade 3-4 neutropenia (OR &#x3d; 2.191; 95% CI: 1.087&#x2013;4.417; <italic>p</italic> &#x3d; 0.028) in 158 esophageal cancer patients receiving docetaxel, cisplatin, and 5-fluorouracil therapy (<xref ref-type="bibr" rid="B85">Nomura et al., 2020</xref>).</p>
<p>Studies have also focused on <italic>ABCB1</italic> rs2032582 (G2677TA, Ala893Ser) (n &#x3d; 7) and <italic>ABCB1</italic> rs1128503(C1236T) (n &#x3d; 6). The two SNPs are associated with altered P-glycoprotein function, in which the Ser893 variant transporter resulted in a 47% lower intracellular digoxin concentration (<italic>p</italic> &#x3c; .002) than did the Ala893 variant <italic>in vitro</italic> (<xref ref-type="bibr" rid="B59">Kim et al., 2001</xref>) and homozygous carriers of <italic>ABCB1</italic> rs1128503(C1236T) polymorphism was significantly correlated with a decreased docetaxel clearance (<xref ref-type="bibr" rid="B6">Bosch et al., 2006</xref>). <italic>ABCB1</italic> rs2032582 (G2677TA, Ala893Ser) displayed differential genotypic distribution between groups with grade 4 neutropenia and grade 1-3 neutropenia in 107 NSCLC patients (<italic>p</italic> &#x3d; 0.030) (<xref ref-type="bibr" rid="B44">Han et al., 2007</xref>). <italic>ABCB1</italic> rs1128503 (C1236T) were significantly associated with grade 3-4 anemia in additive model (OR &#x3d; 1.71; 95% CI: 1.07&#x2013;2.71; <italic>p</italic> &#x3d; 0.023) in 290 ovarian cancer patients (<xref ref-type="bibr" rid="B63">Lambrechts et al., 2015</xref>). Similarly, another study in 112 ovarian cancer patients found that carriers of TT genotype were more frequently experienced grade 1-4 thrombocytopenia compared to those CC or CT genotype (OR &#x3d; 3.50; 95% CI: 1.12&#x2013;10.97; <italic>p</italic> &#x3d; 0.03) (<xref ref-type="bibr" rid="B30">Ferracini et al., 2021</xref>).</p>
</sec>
<sec id="s3-3-2-3">
<title>3.3.2.3 ABCG2 (BCRP)</title>
<p>ABCG2 (breast cancer resistance protein or BCRP) is efflux transporter proteins that play a role in the development of chemoresistance to platinum agents (<xref ref-type="bibr" rid="B25">Ding-Wu et al., 2012</xref>). No association has been shown with the <italic>ABCG2</italic> rs2231142 (<xref ref-type="bibr" rid="B44">Han et al., 2007</xref>; <xref ref-type="bibr" rid="B79">Marsh et al., 2007</xref>; <xref ref-type="bibr" rid="B63">Lambrechts et al., 2015</xref>; <xref ref-type="bibr" rid="B85">Nomura et al., 2020</xref>; <xref ref-type="bibr" rid="B118">Wang et al., 2021</xref>) and <italic>ABCG2</italic> rs2231137 (<xref ref-type="bibr" rid="B44">Han et al., 2007</xref>; <xref ref-type="bibr" rid="B85">Nomura et al., 2020</xref>; <xref ref-type="bibr" rid="B118">Wang et al., 2021</xref>).</p>
</sec>
<sec id="s3-3-2-4">
<title>3.3.2.4 OCT2 (SLC22A2) and MATE1 (SLC47A1)</title>
<p>OCT2 is considered the predominant transporter mediating active accumulation of cisplatin in the kidney. MATE1 is thought to mediate the final step of renal tubular secretion of cisplatin (<xref ref-type="bibr" rid="B35">Giuliano, 2012</xref>). The <italic>OCT2</italic> rs316019 (808G/T, p.270Ala &#x3e; Ser) variant significantly impaired uptake kinetics of endogenous compounds and drugs (<xref ref-type="bibr" rid="B147">Zolk et al., 2009</xref>; <xref ref-type="bibr" rid="B146">Zolk, 2012</xref>). <italic>OCT2</italic> rs316019 (808G/T, p.270Ala &#x3e; Ser) and <italic>MATE1</italic> rs2289669 (G/A) were analyzed in two studies (<xref ref-type="bibr" rid="B51">Iwata et al., 2012</xref>; <xref ref-type="bibr" rid="B94">Qian et al., 2016</xref>). Qian et al. found significant correlations with grade 3-4 hematological toxicity in these two SNPs among 403 NSCLC patients (<xref ref-type="bibr" rid="B94">Qian et al., 2016</xref>).</p>
</sec>
</sec>
<sec id="s3-3-3">
<title>3.3.3 Metabolism</title>
<p>Platinum compounds can be detoxified by conjugation with glutathione through the aid of glutathione S-transferases (GSTs) (<xref ref-type="bibr" rid="B98">R et al., 2000</xref>). GSTP1, GSTM1, and GSTT1 belongs to Human GSTs and were mostly analyzed for the functional polymorphisms in gene regions.</p>
<sec id="s3-3-3-1">
<title>3.3.3.1 GSTP1</title>
<p>Two common nonsynonymous polymorphisms in <italic>GSTP1</italic>, rs1695 (Ile105Val, A313G) and rs1138272 (Ala114Val), were shown to decrease GSTP1 enzyme activity (<xref ref-type="bibr" rid="B83">Moyer et al., 2008</xref>). <italic>GSTP1</italic> rs1695 (Ile105Val, A313G) was the most common studied variant with 18 studies available. Four studies show a protective effect for hematological toxicity. One study in Brazil reported AG or GG genotype was associated with decreased risk of grade 3-4 anemia and grade 3-4 thrombocytopenia in 112 epithelial ovarian cancer patients (<xref ref-type="bibr" rid="B30">Ferracini et al., 2021</xref>). Another study in Korean showed that patients with A/G or G/G genotype showed lower rate of hematological toxicity (13/24, 54.2%) than those with A/A genotype (74/94, 78.7%) among 118 epithelial ovarian cancer patients (<italic>p</italic> &#x3d; 0.015) (<xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>). Bushra et al. found that GG genotype is associated with decreased risk of grade 3-4 anemia (OR &#x3d; 0.29; 95% CI: 0.10&#x2013;0.87; <italic>p</italic> &#x3d; 0.027) and grade 3-4 neutropenia (OR &#x3d; 0.31; 95% CI: 0.10&#x2013;0.96; <italic>p</italic> &#x3d; 0.043) in 285 NSCLC patients in Bangladesh (<xref ref-type="bibr" rid="B7">Bushra et al., 2020</xref>). Perhaps worth to mention is a comprehensive pharmacogenomic analysis in 320 gynecological cancers patients, of which <italic>GSTP1</italic> rs1695 showed the lowest <italic>p</italic>-value against severe hematological toxicity (<italic>p</italic> &#x3d; 0.00034) (<xref ref-type="bibr" rid="B135">Yoshihama et al., 2018</xref>). In contrast, Walia et al. found a significantly increased risk of grade 3-4 anemia with the AG genotype (OR &#x3d; 2.12; 95% CI: 0.97&#x2013;4.62; <italic>p</italic> &#x3d; 0.04) and increased risk of grade 2-4 leukopenia with the GG genotype (OR &#x3d; 2.41; 95% CI: 1.39&#x2013;4.18; <italic>p</italic> &#x3d; 0.001) in 317 North Indian lung cancer patients (<xref ref-type="bibr" rid="B116">Walia et al., 2021</xref>). <xref ref-type="bibr" rid="B70">Liblab et al. (2020)</xref> found that carriers of AG genotype were more frequently experienced grade 2-4 anemia than AA genotype in 52 ovarian cancer patients (81.82% vs. 46.34%, <italic>p</italic> &#x3d; 0.036). Five studies demonstrated no significant association of <italic>GSTP1</italic> rs1138272 (Ala114Val) polymorphism.</p>
</sec>
<sec id="s3-3-3-2">
<title>3.3.3.2 GSTT1 and GSTM1</title>
<p>Gene deletion in GSTT1 and GSTM1 can lead to an absence of enzymatic activity (<xref ref-type="bibr" rid="B90">Pemble et al., 1994</xref>; <xref ref-type="bibr" rid="B129">Xu et al., 1998</xref>). Nine studies showed no effect of <italic>GSTT1</italic> gene deletion on the risk of hematological toxicity. Eight studies analyzed <italic>GSTM1</italic> gene deletion, in which two studies showed a protective effect (<xref ref-type="bibr" rid="B57">Khrunin et al., 2010</xref>; <xref ref-type="bibr" rid="B27">Er&#x10d;ulj et al., 2012</xref>). In 94 malignant mesothelioma patients treated with platinum-based chemotherapy, Patients with homozygous <italic>GSTM1</italic> gene deletion have a significantly decreased risk of grade 2-4 leukopenia compared with those of at least one functional allele (OR &#x3d; 0.43; 95% CI: 0.18&#x2013;0.99; <italic>p</italic> &#x3d; 0.048) (<xref ref-type="bibr" rid="B27">Er&#x10d;ulj et al., 2012</xref>). Another study in 104 ovarian cancer patients that received paclitaxel and carboplatin found carriers of a homozygous <italic>GSTM1</italic> gene deletion were less likely to develop grade 1-4 thrombocytopenia (OR &#x3d; 0.13; 95% CI: 0.03&#x2013;0.62; <italic>p</italic> &#x3d; 0.005) and grade 2-4 anemia (OR &#x3d; 0.29; 95% CI: 0.13&#x2013;0.66; <italic>p</italic> &#x3d; 0.003) than those of functional GSTM1 variants (<xref ref-type="bibr" rid="B57">Khrunin et al., 2010</xref>).</p>
</sec>
</sec>
<sec id="s3-3-4">
<title>3.3.4 NER pathway</title>
<p>The bulky DNA intra-strand adducts generated by platinum are mainly repaired by the nucleotide-excision repair (NER) pathway (<xref ref-type="bibr" rid="B17">Clarissa Ribeiro Reily et al., 2018</xref>).</p>
<sec id="s3-3-4-1">
<title>3.3.4.1 ERCC1</title>
<p>ERCC1 interact with XPF to make an incision at the damaged DNA lesion in NER pathway. <italic>ERCC1</italic> rs11615 (C118T, Asn118Asn) (n &#x3d; 19) and <italic>ERCC1</italic> rs3212986 (C8092A) (n &#x3d; 12) have been wildly studied. <italic>ERCC1</italic> rs11615 reduces the transcription and mRNA levels of <italic>ERCC1</italic>, resulting in lower ERCC1 expression (<xref ref-type="bibr" rid="B136">Yu et al., 2000</xref>). <italic>ERCC1</italic> rs3212986 resides in the 30-untranslated region that might affect mRNA stability (<xref ref-type="bibr" rid="B14">Chen et al., 2000</xref>). Four studies reported a significantly increased risk with <italic>ERCC1</italic> rs11615 (C118T, Asn118Asn). In a study of 292 colon cancer patients receiving adjuvant oxaliplatin plus leucovorin plus 5-fluorouracil (FOLFOX) chemotherapy, TT genotype was more prone to develop grade 3-4 neutropenia (OR &#x3d; 4.58, 95% CI: 1.20&#x2013;17.40, <italic>p</italic> &#x3d; 0.026) (<xref ref-type="bibr" rid="B65">Lee et al., 2013</xref>). Another study in 119 testicular cancer patients also reported an increased risk of grade 3-4 febrile neutropenia caused by bleomycin, etoposide, and cisplatin (BEP) chemotherapy in TT genotype (OR &#x3d; 4.89; 95% CI: 1.06&#x2013;22.56; <italic>p</italic> &#x3d; 0.042) (<xref ref-type="bibr" rid="B64">Lavanderos et al., 2019</xref>). <italic>ERCC1</italic> rs11615 was associated with an increased risk of grade 3-4 anemia in 290 ovarian cancer patients (OR &#x3d; 1.61; 95% CI: 1.04&#x2013;2.50; <italic>p</italic> &#x3d; 0.031) (<xref ref-type="bibr" rid="B63">Lambrechts et al., 2015</xref>) and 437 NSCLC patients (OR &#x3d; 2.230; 95% CI: 1.041&#x2013;4.775; <italic>p</italic> &#x3d; 0.039) (<xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>). On the contrary, <xref ref-type="bibr" rid="B19">Cortejoso et al. (2013)</xref> found individuals carrying T allele had a reduced risk of grade 3-4 neutropenia in 106 colon cancer patients (OR &#x3d; 0.205; 95% CI: 0.061&#x2013;0.690; <italic>p</italic> &#x3d; 0.010). As for <italic>ERCC1</italic> rs3212986(C8092A), two studies reported a decreased risk. Zheng et al. found that <italic>ERCC1</italic> rs3212986 was significantly associated with a reduced risk of grade 3-4 hematologic toxicity in recessive model in 437 NSCLC patients (OR &#x3d; 0.326; 95% CI: 0.123&#x2013;0.861; <italic>p</italic> &#x3d; 0.024) (<xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>). <xref ref-type="bibr" rid="B27">Er&#x10d;ulj et al. (2012)</xref> reported that patients carrying A allele had a lower risk of grade 2-4 leukopenia in 94 malignant mesothelioma patients (OR &#x3d; 0.18; 95% CI: 0.04&#x2013;0.86; <italic>p</italic> &#x3d; 0.032). No association has been established between <italic>ERCC1</italic> rs3212961 (17677G&#x3e;T) and the development of hematologic toxicity (<xref ref-type="bibr" rid="B79">Marsh et al., 2007</xref>; <xref ref-type="bibr" rid="B63">Lambrechts et al., 2015</xref>; <xref ref-type="bibr" rid="B108">Song et al., 2017</xref>).</p>
</sec>
<sec id="s3-3-4-2">
<title>3.3.4.2 ERCC2/XPD</title>
<p>ERCC2 (XPD) is a helicase that can unwind the DNA strands to facilitate the binding of other NER proteins. <italic>ERCC2</italic> rs13181 (Lys751Gln), rs1799793(Asp312Asn), rs238406 (C22541A, Arg156Arg), rs1052555 (Asp711Asp) have been evaluated in 17 studies, 13 studies, five studies and three studies respectively. <italic>ERCC2</italic> rs13181(Lys751Gln) can alter mRNA transcription levels, leading to reduced levels of <italic>ERCC2</italic> mRNA(82)<italic>.</italic> For <italic>ERCC2</italic> rs13181 (Lys751Gln), grade 2-4 neutropenia was more frequent among individual with 751 Lys/Lys genotype in 62 NSCLC patients treated with cisplatin and docetaxel (<italic>p</italic> &#x3d; 0.04) (<xref ref-type="bibr" rid="B50">Isla et al., 2004</xref>).</p>
<p>
<italic>ERCC2</italic> rs1799793 (Asp312Asn) is associated with significantly decreased constitutive XPD mRNA levels in lymphocytes of healthy subjects (<xref ref-type="bibr" rid="B126">Wolfe et al., 2007</xref>). Results on rs1799793 (Asp312Asn) have not been consistent. Er&#x10d;ulj et al. found patients carrying 312Asp/Asn and 312Asn/Asn genotype had a lower risk of grade 1-4 thrombocytopenia in 94 malignant mesothelioma patients (OR &#x3d; 0.15; 95% CI: 0.04&#x2013;0.61; <italic>p</italic> &#x3d; 0.008) (<xref ref-type="bibr" rid="B27">Er&#x10d;ulj et al., 2012</xref>). Whereas, <xref ref-type="bibr" rid="B57">Khrunin et al. (2010)</xref> found patients carrying Asp/Asn genotype were more prone to grade 1-4 thrombocytopenia (OR &#x3d; 4.05; 95% CI: 1.21&#x2013;13.58; <italic>p</italic> &#x3d; 0.027) and grade 2-4 anemia (OR &#x3d; 2.32; 95% CI: 1.05&#x2013;5.13; <italic>p</italic> &#x3d; 0.048) in 104 ovarian cancer patients. <italic>ERCC2</italic> rs238406(C22541A, Arg156Arg) can reduce the levels of mRNA and ultimately affect XPD activity and function (<xref ref-type="bibr" rid="B126">Wolfe et al., 2007</xref>). The incidence of grade 3-4 hematologic toxicity (OR &#x3d; 3.24; 95% CI: 1.35&#x2013;7.78; <italic>p</italic> &#x3d; 0.009) and grade 3-4 leukopenia (OR &#x3d; 4.88; 95% CI: 1.67&#x2013;14.26; <italic>p</italic> &#x3d; 0.005) was significantly higher in variant homozygotes AA genotype, when compared with CC genotype in 209 NSCLC patients (<xref ref-type="bibr" rid="B128">Wu et al., 2009</xref>). Likewise, another study in 119 testicular cancer patients showed the increased risk of grade 3-4 leukopenia with the AA or CA genotype (OR &#x3d; 4.09; 95% CI: 1.04&#x2013;15.99; <italic>p</italic> &#x3d; 0.043) (<xref ref-type="bibr" rid="B64">Lavanderos et al., 2019</xref>). Studies on <italic>ERCC2</italic> rs1052555 (Asp711Asp) (n &#x3d; 3) showed no significant difference (<xref ref-type="bibr" rid="B128">Wu et al., 2009</xref>; <xref ref-type="bibr" rid="B108">Song et al., 2017</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>).</p>
</sec>
<sec id="s3-3-4-3">
<title>3.3.4.3 ERCC4/XPF</title>
<p>ERCC4/XPF participates in the removal of damaged DNA strands by acting as an endonuclease with ERCC1. Of two studies in <italic>ERCC4</italic> rs1799801 (T&#x3e;C, Ser835Ser) (<xref ref-type="bibr" rid="B108">Song et al., 2017</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>), one study in 437 NSCLC patients demonstrated an association of the <italic>ERCC4</italic> rs1799801 with grade 3-4 hematologic toxicity in additive model (OR &#x3d; 1.555; 95% CI: 1.041&#x2013;2.323; <italic>p</italic> &#x3d; 0.031) and grade 3-4 thrombocytopenia in dominant model (OR &#x3d; 3.562; 95% CI: 1.513&#x2013;8.390; <italic>p</italic> &#x3d; 0.004) (<xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>).</p>
</sec>
<sec id="s3-3-4-4">
<title>3.3.4.4 XPC</title>
<p>XPC cooperates with RAD23B to recognize DNA lesions and start the initial step of damage recognition. Three studies concentrate on <italic>XPC</italic> rs2228001(A&#x3e;C, Lys939Gln) (<xref ref-type="bibr" rid="B108">Song et al., 2017</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>; <xref ref-type="bibr" rid="B7">Bushra et al., 2020</xref>). <italic>XPC</italic> rs2228001(A&#x3e;C, Lys939Gln) was associated with lower DNA repair capacity (<xref ref-type="bibr" rid="B145">Zhu et al., 2008</xref>). In 285 Bangladesh NSCLC patients, carriers of <italic>XPC</italic> rs2228001 AC or CC genotypes showed significant suffering from grade 3-4 neutropenia (OR &#x3d; 2.63; 95% CI: 1.41&#x2013;4.90; <italic>p</italic> &#x3d; 0.002), while those harboring CC genotypes are less likely to develop grade 3-4 anemia, compared with AA genotype carriers (OR &#x3d; 0.18; 95% CI: 0.04&#x2013;0.82; <italic>p</italic> &#x3d; 0.027) (<xref ref-type="bibr" rid="B7">Bushra et al., 2020</xref>). Another study conducted in 437 Chinese NSCLC patients show <italic>XPC</italic> rs2228001 is associated with an increased risk of grade 3-4 leukocytopenia in dominant model (OR &#x3d; 2.217; 95% CI: 1.054&#x2013;4.665; <italic>p</italic> &#x3d; 0.036) (<xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>).</p>
</sec>
<sec id="s3-3-4-5">
<title>3.3.4.5 ERCC5/XPG</title>
<p>ERCC5 (XPG) encodes a structure-specific endonuclease that can cleave the 3&#x2b9;-end of damaged DNA lesions. Two studies focus on <italic>XPG</italic> rs1047768(A&#x3e;C, Lys939Gln) and rs17655(A&#x3e;C, Lys939Gln). Zheng et al. found a significant association of <italic>XPG</italic> rs1047768 with grade 3-4 leukocytopenia in additive model (OR &#x3d; 1.701; 95% CI: 1.021&#x2013;2.835; <italic>p</italic> &#x3d; 0.041) and <italic>XPG</italic> rs17655 with grade 3-4 thrombocytopenia in additive model (OR &#x3d; 2.165; 95% CI: 1.191&#x2013;3.938; <italic>p</italic> &#x3d; 0.011) (<xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>). The other study reported no association with these two investigated SNPs (<xref ref-type="bibr" rid="B108">Song et al., 2017</xref>).</p>
</sec>
<sec id="s3-3-4-6">
<title>3.3.4.6 Other NER genes</title>
<p>
<italic>XPA</italic> rs1800975, <italic>RPA1</italic> rs17734, <italic>RPA1</italic> rs12727 and <italic>CCNH</italic> rs2230641 (<xref ref-type="bibr" rid="B108">Song et al., 2017</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>) were examined twice and showed no significant associations.</p>
</sec>
</sec>
<sec id="s3-3-5">
<title>3.3.5 BER pathway</title>
<p>The base excision repair (BER) pathway is mainly responsible for removing the oxidative DNA lesions generated by platinum drug exposure (<xref ref-type="bibr" rid="B52">Jana et al., 2018</xref>).</p>
<sec id="s3-3-5-1">
<title>3.3.5.1 XRCC1</title>
<p>XRCC1 acts as a central scaffolding protein to finish the final steps of BER. <italic>XPCC1</italic> rs25487 (G&#x3e;A, Arg399Gln) can cause missense mutation in the coding region, leading to decreased damage DNA repair activity (<xref ref-type="bibr" rid="B122">Wang et al., 2003</xref>; <xref ref-type="bibr" rid="B115">Vodicka et al., 2004</xref>). 14 studies investigated a link of <italic>XPCC1</italic> rs25487 (G&#x3e;A, Arg399Gln) with hematological toxicity and results have not been consistent. In a study of 285 NSCLC patients, <italic>XRCC1</italic> rs25487 polymorphism showed significant associations with increased risk of grade 3-4 anemia, grade 3-4 neutropenia, grade 3-4 leukopenia and grade 3-4 thrombocytopenia (<xref ref-type="bibr" rid="B7">Bushra et al., 2020</xref>). A higher risk of grade 3-4 hematologic toxicity was also observed in AG and GG carriers in a cohort of 235 NSCLC patients (OR &#x3d; 2.135; 95% CI: 1.207&#x2013;3.777; <italic>p</italic> &#x3d; 0.009) (<xref ref-type="bibr" rid="B92">Peng et al., 2014</xref>). In keeping with this, <italic>XRCC1</italic> rs25487 was identified as risk factors for grade 3-4 leukocytopenia in recessive model (OR &#x3d; 2.841; 95% CI: 1.051&#x2013;7.681; <italic>p</italic> &#x3d; 0.040), grade 3-4 thrombocytopenia in additive model (OR &#x3d; 2.033; 95% CI: 1.113&#x2013;3.715; <italic>p</italic> &#x3d; 0.021) in discovery cohort of 437 NSCLC patients (<xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>). In contrast, AA or AG carriers had a decreased risk of grade 1-4 lymphopenia as observed in 94 NSCLC patients (OR &#x3d; 0.323; 95% CI: 0.121&#x2013;0.862; <italic>p</italic> &#x3d; 0.024) (<xref ref-type="bibr" rid="B23">Deng et al., 2015</xref>). In 104 ovarian cancer that received cisplatin and cyclophosphamide, an increased risk of grade 3-4 neutropenia was found in GG wildtype carriers (OR &#x3d; 3.02; 95% CI: 1.33&#x2013;6.88; <italic>p</italic> &#x3d; 0.009) (<xref ref-type="bibr" rid="B57">Khrunin et al., 2010</xref>). Other studies failed to reveal a positive association.</p>
<p>
<italic>XPCC1</italic> rs1799782 (Arg194Trp) can leading to decreased DNA repair activity (<xref ref-type="bibr" rid="B122">Wang et al., 2003</xref>)<italic>. XPCC1</italic> rs1799782 (Arg194Trp) (n &#x3d; 4) (<xref ref-type="bibr" rid="B123">Wang et al., 2008</xref>; <xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>; <xref ref-type="bibr" rid="B57">Khrunin et al., 2010</xref>; <xref ref-type="bibr" rid="B65">Lee et al., 2013</xref>) and <italic>XPCC1</italic> rs25489 (Arg280His) (n &#x3d; 3) (<xref ref-type="bibr" rid="B57">Khrunin et al., 2010</xref>; <xref ref-type="bibr" rid="B65">Lee et al., 2013</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>) showed no significant difference with hematological toxicity.</p>
</sec>
<sec id="s3-3-5-2">
<title>3.3.5.2 APE1 and OGG1</title>
<p>APE1 and OGG1 are key component in the BER pathway. Two studies examined <italic>APE1</italic> rs1130409 (Asp148Glu) and <italic>OGG1</italic> rs1052133 (Ser326Cys) (<xref ref-type="bibr" rid="B92">Peng et al., 2014</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>). <italic>APE1</italic> rs1130409(Asp148Glu) variant exhibiting normal <italic>in vitro</italic> nuclease capacity (<xref ref-type="bibr" rid="B22">Daviet et al., 2007</xref>; <xref ref-type="bibr" rid="B125">Wilson et al., 2011</xref>) and <italic>OGG1</italic> rs1052133(Ser326Cys) polymorphism negatively impacts OGG1 function (<xref ref-type="bibr" rid="B125">Wilson et al., 2011</xref>). <italic>APE1</italic> rs1130409 was associated with a decreased risk of grade 3-4 leukocytopenia (OR &#x3d; 0.460; 95% CI: 0.241&#x2013;0.879; <italic>p</italic> &#x3d; 0.019) and grade 3-4 neutropenia (OR &#x3d; 0.557; 95% CI: 0.321&#x2013;0.967; <italic>p</italic> &#x3d; 0.038) in dominant model (<xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>). <italic>OGG1</italic> rs1052133 failed to show significant association with hematological toxicity (<xref ref-type="bibr" rid="B92">Peng et al., 2014</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>).</p>
</sec>
</sec>
<sec id="s3-3-6">
<title>3.3.6 DSB pathway</title>
<p>Homologous recombination (HR) and non-homologous and joining pathways are responsible for repairing the DSBs generated by platinum-induced ICLs which are the most hazardous type of DNA damage. XRCC3 are one of the crucial proteins involved in mediating the HR pathway (<xref ref-type="bibr" rid="B33">Giovanna and Massimo, 2019</xref>). <italic>XRCC3</italic> rs861539(C&#x3e;T, Thr241Met) was show to reduce DNA damage repair capacity (<xref ref-type="bibr" rid="B80">Matullo et al., 2001</xref>). However, no association was detected in three analyses on <italic>XRCC3</italic> rs861539 (Thr241Met) (<xref ref-type="bibr" rid="B76">Ludovini et al., 2011</xref>; <xref ref-type="bibr" rid="B101">Ruzzo et al., 2014</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>).</p>
</sec>
<sec id="s3-3-7">
<title>3.3.7 TLS</title>
<p>TLS is performed by a series of low-fidelity polymerases to tolerate platinum-induced DNA lesions (<xref ref-type="bibr" rid="B112">The Vinh and Orlando, 2010</xref>). <italic>REV3L</italic> rs462779 (<xref ref-type="bibr" rid="B39">Gori&#x10d;ar et al., 2014</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>), <italic>REV3L</italic> rs465646 (<xref ref-type="bibr" rid="B39">Gori&#x10d;ar et al., 2014</xref>; <xref ref-type="bibr" rid="B132">Ye et al., 2015</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>), <italic>REV7</italic> rs746218 (<xref ref-type="bibr" rid="B132">Ye et al., 2015</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>), <italic>REV7</italic> rs2233006 (<xref ref-type="bibr" rid="B132">Ye et al., 2015</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>), <italic>REV1</italic> rs3087386 (<xref ref-type="bibr" rid="B39">Gori&#x10d;ar et al., 2014</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>) and <italic>Rad18</italic> rs373572 (<xref ref-type="bibr" rid="B16">Chu et al., 2016</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>) were analyzed in more than one study. <italic>REV3</italic> rs465646 were associated with grade 3-4 hematologic toxicity in 663 NSCLC patients (OR &#x3d; 2.54; 95% CI: 1.17&#x2013;5.42; <italic>p</italic> &#x3d; 0.016) (<xref ref-type="bibr" rid="B132">Ye et al., 2015</xref>). In a study of 139 malignant mesothelioma patients receiving cisplatin-based chemotherapy, carriers of the <italic>REV1</italic> rs3087386 A allele were less prone to develop grade 2-4 neutropenia (OR &#x3d; 0.38; 95% CI: 0.17&#x2013;0.84; <italic>p</italic> &#x3d; 0.017) (<xref ref-type="bibr" rid="B39">Gori&#x10d;ar et al., 2014</xref>). Other studies show no significant associations.</p>
</sec>
<sec id="s3-3-8">
<title>3.3.8 DNA synthesis</title>
<sec id="s3-3-8-1">
<title>3.3.8.1 MTHFR</title>
<p>MTHFR is involved in folate metabolism, essential for the synthesis of nucleic acids and amino acids. Two common nonsynonymous polymorphisms in MTHFR, rs1801133 (C677T, Ala222Val) and rs1801131 (A1298C, Glu429Ala) were shown to decrease MTHFR enzyme activity <italic>in vitro</italic> (<xref ref-type="bibr" rid="B114">van der Put et al., 1998</xref>). These two SNPs were analyzed in six studies (<xref ref-type="bibr" rid="B65">Lee et al., 2013</xref>; <xref ref-type="bibr" rid="B18">Corrigan et al., 2014</xref>; <xref ref-type="bibr" rid="B56">Kanazawa et al., 2014</xref>; <xref ref-type="bibr" rid="B68">Li et al., 2014</xref>; <xref ref-type="bibr" rid="B101">Ruzzo et al., 2014</xref>; <xref ref-type="bibr" rid="B117">Walia et al., 2022</xref>). The results for <italic>MTHFR</italic> rs1801133 (C677T, Ala222Val) were inconsistent. An increased risk of grade 1-3 neutropenia was detected in carriers of the T allele (OR &#x3d; 4.45; 95% CI: 1.28&#x2013;15.43; <italic>p</italic> &#x3d; 0.019) among 123 lung adenocarcinoma patients treated with platinum and pemetrexed chemotherapy (<xref ref-type="bibr" rid="B117">Walia et al., 2022</xref>). Likewise, carriers of the TT genotype were more likely to develop grade 3-4 neutropenia compared with those carrying CC and CT genotype in 292 colon cancer patients (OR &#x3d; 2.32, 95% CI: 1.19&#x2013;4.55, <italic>p</italic> &#x3d; 0.014) (<xref ref-type="bibr" rid="B65">Lee et al., 2013</xref>). While, the heterozygote CT genotype show a protective effect for grade 3-4 thrombocytopenia in Li et al.&#x2019;s study of 1004 NSCLC patients (OR &#x3d; 0.40; 95% CI: 0.19&#x2013;0.85; <italic>p</italic> &#x3d; 0.016) (<xref ref-type="bibr" rid="B68">Li et al., 2014</xref>). <italic>MTHFR</italic> rs1801131 (A1298C, Glu429Ala) showed no effect on risk of hematological toxicity.</p>
</sec>
<sec id="s3-3-8-2">
<title>3.3.8.2 RRM1</title>
<p>RRM1 encodes the regulatory subunit of ribonucleotide reductase and is involved in the production of deoxyribonucleotides during DNA synthesis. <italic>RRM1</italic> &#x2013; 37A allele impacted promoter activity with increased RRM1 mRNA expression <italic>in vitro</italic> (<xref ref-type="bibr" rid="B2">Bepler et al., 2005</xref>; <xref ref-type="bibr" rid="B100">Rodriguez et al., 2011</xref>). <italic>RRM1</italic> rs12806698 (&#x2212;37C/A) was suggested as a candidate risk factor for grade 3-4 leukocytopenia (OR &#x3d; 5.095; 95% CI: 2.132&#x2013;12.170; <italic>p</italic> &#x3d; 0.0002) and grade 3-4 neutropenia (OR &#x3d; 2.561; 95% CI: 1.075&#x2013;6.099; <italic>p</italic> &#x3d; 0.034) in recessive model in 437 NSCLC patients (<xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>), while in another study of 63 NSCLC patients, grade 2-4 leukopenia was more frequent among patients with wild-type <italic>RRM1</italic> rs12806698 CC genotype than carriers of CA genotype (37% versus 10%, <italic>p</italic> &#x3d; 0.05) (<xref ref-type="bibr" rid="B50">Isla et al., 2004</xref>).</p>
</sec>
</sec>
<sec id="s3-3-9">
<title>3.3.9 Apoptosis</title>
<sec id="s3-3-9-1">
<title>3.3.9.1 MDM2</title>
<p>
<italic>MDM2</italic> rs2279744 (309T&#x3e;G) resulted in higher levels of MDM2 RNA and protein and the subsequent attenuation of the p53 DNA damage response (<xref ref-type="bibr" rid="B5">Bond et al., 2004</xref>). For <italic>MDM2</italic> rs2279744 (309T&#x3e;G) (n &#x3d; 4), two studies in lung cancer patients observed a protective effect for grade 3-4 thrombocytopenia (OR &#x3d; 0.472; 95% CI: 0.257&#x2013;0.866; <italic>p</italic> &#x3d; 0.015) (<xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>) and grade 3-4 neutropenia (OR &#x3d; 0.27; 95% CI: 0.08763&#x2013;0.8859; <italic>p</italic> &#x3d; 0.030) respectively (<xref ref-type="bibr" rid="B120">Wang et al., 2014</xref>). Another study in 292 lung adenocarcinoma patients show opposite results that <italic>MDM2</italic> rs2279744 was associated with an increased risk of grade 3-4 hematologic toxicity in recessive model (OR &#x3d; 2.128; 95% CI: 1.198&#x2013;3.777; <italic>p</italic> &#x3d; 0.010) (<xref ref-type="bibr" rid="B42">Guo et al., 2016</xref>).</p>
</sec>
<sec id="s3-3-9-2">
<title>3.3.9.2 TP 53</title>
<p>TP53 (p53) is a key regulator of cell cycle control and DNA damage response as well as apoptosis initiation. <italic>TP53</italic> rs1042522 (Arg72Pro) Arg72 variant is more efficient than the Pro72 variant in inducing apoptosis (<xref ref-type="bibr" rid="B26">Dumont et al., 2003</xref>). <italic>TP53</italic> rs1042522 (Arg72Pro) was associated with an increased risk of grade 3-4 neutropenia in recessive model (OR &#x3d; 3.44; 95% CI: 1.302&#x2013;9.111; <italic>p</italic> &#x3d; 0.012) in 119 SCLC patients treated with cisplatin and etoposide (<xref ref-type="bibr" rid="B120">Wang et al., 2014</xref>). Another study in 104 ovarian cancer patients showed similar result that patients carrying GG genotype were prone to experience grade 3-4 neutropenia, compared with CC &#x2b; CG genotype (OR &#x3d; 8.57; 95% CI: 1.05&#x2013;69.8; <italic>p</italic> &#x3d; 0.023) (<xref ref-type="bibr" rid="B57">Khrunin et al., 2010</xref>). The remaining studies (n &#x3d; 7) showed no significant difference.</p>
</sec>
</sec>
</sec>
<sec id="s3-4">
<title>3.4 Significant associations in other less commonly investigated variants</title>
<p>The array of SNPs that investigated only once are listed in <xref ref-type="sec" rid="s11">Supplementary Table S8</xref>. Lots of studies analyzed those less commonly investigated variants in main candidate genes such as <italic>SLC31A1 (CTR1)</italic> (<xref ref-type="bibr" rid="B131">Xu et al., 2012</xref>; <xref ref-type="bibr" rid="B109">Sun et al., 2018</xref>), <italic>ATP7A</italic> (<xref ref-type="bibr" rid="B23">Deng et al., 2015</xref>; <xref ref-type="bibr" rid="B69">Li et al., 2018</xref>), <italic>ATP7B</italic> (<xref ref-type="bibr" rid="B69">Li et al., 2018</xref>), <italic>ABCC2</italic> (<xref ref-type="bibr" rid="B101">Ruzzo et al., 2014</xref>), <italic>ABCB1</italic> (<xref ref-type="bibr" rid="B15">Chen et al., 2010</xref>; <xref ref-type="bibr" rid="B12">Chen et al., 2016</xref>), <italic>ABCG2</italic> (<xref ref-type="bibr" rid="B12">Chen et al., 2016</xref>; <xref ref-type="bibr" rid="B118">Wang et al., 2021</xref>), <italic>OCT2</italic> (<xref ref-type="bibr" rid="B12">Chen et al., 2016</xref>; <xref ref-type="bibr" rid="B94">Qian et al., 2016</xref>), <italic>MDM2</italic> (<xref ref-type="bibr" rid="B141">Zheng et al., 2014</xref>; <xref ref-type="bibr" rid="B95">Qian et al., 2015</xref>), <italic>TP53</italic> (<xref ref-type="bibr" rid="B57">Khrunin et al., 2010</xref>) or tagSNPs on genes that are not directly affect the influx, efflux and metabolism of platinum agent or play as mediators or modulators of center cellular activities. Those genes and the functions were listed in <xref ref-type="sec" rid="s11">Supplementary Table S8</xref>, including the transport genes (<italic>SLCs</italic>, <italic>AQP2</italic>, <italic>AQP9</italic>, <italic>TMEM205</italic>, <italic>SIRT1</italic>, <italic>ABCC1</italic>, <italic>MVP</italic>, <italic>AQP1</italic>) (<xref ref-type="bibr" rid="B12">Chen et al., 2016</xref>; <xref ref-type="bibr" rid="B104">Senk et al., 2019</xref>), Metabolism gene (<italic>CYP2E1</italic>, <italic>GSTA1</italic>, <italic>GSTM3</italic>, <italic>AGXT</italic>, <italic>MAPT</italic>, <italic>MPO</italic>) (<xref ref-type="bibr" rid="B79">Marsh et al., 2007</xref>; <xref ref-type="bibr" rid="B57">Khrunin et al., 2010</xref>; <xref ref-type="bibr" rid="B65">Lee et al., 2013</xref>), MicroRNAs (<xref ref-type="bibr" rid="B138">Zhan et al., 2012</xref>; <xref ref-type="bibr" rid="B28">Fang et al., 2017</xref>), Long Non-Coding RNA (<xref ref-type="bibr" rid="B48">Hu et al., 2016</xref>; <xref ref-type="bibr" rid="B38">Gong et al., 2017</xref>). Apoptosis-related genes (<italic>BCL2</italic>, <italic>BAX</italic>, <italic>CASP3</italic>, <italic>CASP8</italic>, <italic>CASP10</italic>, <italic>TNF&#x3b1;</italic> and <italic>MIF</italic>) (<xref ref-type="bibr" rid="B41">Gu et al., 2012</xref>; <xref ref-type="bibr" rid="B96">Qian et al., 2012</xref>; <xref ref-type="bibr" rid="B72">Liu D. et al., 2017a</xref>), <italic>EPO</italic> (<xref ref-type="bibr" rid="B142">Zheng et al., 2021</xref>), <italic>VCP</italic> (<xref ref-type="bibr" rid="B91">Peng et al., 2013</xref>), <italic>STAT3</italic> (<xref ref-type="bibr" rid="B37">Gong et al., 2019</xref>), <italic>WISP1</italic> (<xref ref-type="bibr" rid="B13">Chen et al., 2014</xref>), <italic>TERT</italic> (<xref ref-type="bibr" rid="B139">Zhao et al., 2015</xref>), <italic>CHEK2</italic> (<xref ref-type="bibr" rid="B130">Xu et al., 2016</xref>), <italic>MMP-2</italic> (<xref ref-type="bibr" rid="B140">Zhao et al., 2012</xref>), <italic>RICTOR</italic> (<xref ref-type="bibr" rid="B119">Wang et al., 2016</xref>), <italic>eIF3 a</italic> (<xref ref-type="bibr" rid="B134">Yin et al., 2015</xref>), HSP genes and Rho family genes (<xref ref-type="bibr" rid="B148">Zou et al., 2016</xref>), CDC25 family genes (<xref ref-type="bibr" rid="B8">Cai et al., 2014</xref>), The JNK and P38 MAPK pathways genes (<xref ref-type="bibr" rid="B53">Jia et al., 2016</xref>), MIF signaling pathway (<xref ref-type="bibr" rid="B111">Tan et al., 2014</xref>). As to DNA repair pathway, there were studies focus on tagSNPs in less investigated NER genes (<xref ref-type="bibr" rid="B12">Chen et al., 2016</xref>; <xref ref-type="bibr" rid="B108">Song et al., 2017</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>) and BER genes (<xref ref-type="bibr" rid="B92">Peng et al., 2014</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>). DNA repair pathway that not directly involved in repairing platinum-induced DNA lesions like MMR (<xref ref-type="bibr" rid="B73">Liu JY. et al., 2017b</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>), DSB (<xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>), TLS (<xref ref-type="bibr" rid="B39">Gori&#x10d;ar et al., 2014</xref>; <xref ref-type="bibr" rid="B107">Shao et al., 2014</xref>; <xref ref-type="bibr" rid="B132">Ye et al., 2015</xref>; <xref ref-type="bibr" rid="B16">Chu et al., 2016</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>), FA pathway (<xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>), have received more attention recently. Some significant association was found, while these SNPs were not previously analyzed and should be validated in future studies.</p>
</sec>
<sec id="s3-5">
<title>3.5 High throughput researches</title>
<p>Four studies are derived from the same cohort in Sweden population of 215 NSCLC patients treated with gemcitabine/carboplatin chemotherapy (<xref ref-type="bibr" rid="B40">Gr&#xe9;en et al., 2016</xref>; <xref ref-type="bibr" rid="B110">Svedberg et al., 2020</xref>; <xref ref-type="bibr" rid="B4">Bj&#xf6;rn et al., 2020a</xref>; <xref ref-type="bibr" rid="B3">Bj&#xf6;rn et al., 2020b</xref>). Three of them were whole-exome sequence studies concentrating of gemcitabine/carboplatin-induced grade 3-4 thrombocytopenia (<xref ref-type="bibr" rid="B40">Gr&#xe9;en et al., 2016</xref>; <xref ref-type="bibr" rid="B4">Bj&#xf6;rn et al., 2020a</xref>), leukopenia (<xref ref-type="bibr" rid="B110">Svedberg et al., 2020</xref>) and neutropenia (<xref ref-type="bibr" rid="B40">Gr&#xe9;en et al., 2016</xref>; <xref ref-type="bibr" rid="B110">Svedberg et al., 2020</xref>). The fourth study performed a GWAS in a subset of 96 patients (<xref ref-type="bibr" rid="B3">Bj&#xf6;rn et al., 2020b</xref>). These studies identified and validated several genetic variations, genes and hematopoiesis-related pathways to be potential significance and created weighted genetic risk score (wGRS) prediction models for predicting the risk of chemotherapy-induced hematological toxicity. There were GWAS concentrating on NSCLC (<xref ref-type="bibr" rid="B10">Cao et al., 2016</xref>), cervical cancer (<xref ref-type="bibr" rid="B49">Huang et al., 2015</xref>), and unclassified carcinomas (<xref ref-type="bibr" rid="B74">Low et al., 2013</xref>). A list of novel genetic variants such as rs13014982 at 2q24.3 and rs9909179 at 17p12 were identified (<xref ref-type="bibr" rid="B10">Cao et al., 2016</xref>) and the artificial neural networks model based on the multiple risk factors were constructed (<xref ref-type="bibr" rid="B49">Huang et al., 2015</xref>). Yin et al. developed a strategy to establish a predicted model of toxicity integrating both genetic and clinical factors using DM techniques (<xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>).</p>
</sec>
</sec>
<sec sec-type="discussion" id="s4">
<title>4 Discussion</title>
<sec id="s4-1">
<title>4.1 Main findings</title>
<p>This systematic review has reported and evaluated the findings of published studies that investigated the genetic associations with hematological toxicities in the cancer patients receiving platinum-based chemotherapy. We found that <italic>ABCC2</italic> rs12762549, <italic>ABCB1</italic> rs1045642, <italic>ABCB1</italic> rs1128503, <italic>GSTP1</italic> rs1695, <italic>GSTM1</italic> gene deletion, <italic>ERCC1</italic> rs11615, <italic>ERCC1</italic> rs3212986, <italic>ERCC2</italic> rs238406, <italic>ERCC2</italic> rs1799793, <italic>XPC</italic> rs2228001, <italic>XPCC1</italic> rs25487, <italic>MTHFR</italic> rs1801133, <italic>MDM2</italic> rs2279744, <italic>RRM1</italic> rs12806698, <italic>TP53</italic> rs1042522 show positive associations in more than two studies, but most associations were not consistently replicated across the reviewed studies. Among them, <italic>ABCB1</italic> rs1128503, <italic>GSTP1</italic> rs1695, <italic>GSTM1</italic> gene deletion, <italic>ERCC1</italic> rs11615, <italic>ERCC1</italic> rs3212986, <italic>ERCC2</italic> rs238406, <italic>XPC</italic> rs2228001, <italic>XPCC1</italic> rs25487, <italic>MTHFR</italic> rs1801133, <italic>MDM2</italic> rs2279744, <italic>TP53</italic> rs1042522 had consistent results across at least two independent populations. These genetic variants may provide insights into the molecular mechanisms towards platinum-induced hematological toxicities (<xref ref-type="bibr" rid="B97">Qihai et al., 2023</xref>).</p>
<p>It&#x27;s also worth mentioning that <italic>GSTP1</italic> rs1695 (A313G, Ile105Val) show significant association in six studies. Among them, four studies show protective role of <italic>GSTP1</italic> rs1695 against platinum-induced hematological toxicities, including a comprehensive analysis that targeted resequencing of 100 notable pharmacokinetics-related genes in which <italic>GSTP1</italic> rs1695 showed the smallest <italic>p</italic>-value (<italic>p</italic> &#x3d; 0.00034) (<xref ref-type="bibr" rid="B135">Yoshihama et al., 2018</xref>). Positive associations of <italic>GSTP1</italic> rs1695 with increased risk of platinum-induced hematological toxicity was found in two meta-analysis (<xref ref-type="bibr" rid="B77">Lv et al., 2018</xref>; <xref ref-type="bibr" rid="B60">Kim et al., 2022</xref>), while these two meta-analysis studies face the limitations of insufficient data availability. Alteration of DNA repair ability might play an important role in the development of platinum-induced hematological toxicity. Genetic variants in the candidate NER genes may affect the repair function and are most promising in predicting platinum-related hematological toxicity, since it is the main pathway responsible of repairing the bulky DNA intra-strand adducts generated by platinum agents (<xref ref-type="bibr" rid="B46">Hilary et al., 2024</xref>). <italic>ERCC1</italic> rs11615 (C118T, Asn118Asn) and <italic>ERCC1</italic> rs3212986 (C8092A) are two common variant that affect ERCC1 (key enzyme in NER pathway) mRNA expression or mRNA stability (<xref ref-type="bibr" rid="B14">Chen et al., 2000</xref>; <xref ref-type="bibr" rid="B136">Yu et al., 2000</xref>). <italic>ERCC1</italic> rs11615 present consistent results with increased risk of grade 3-4 neutropenia or anemia in four studies, and <italic>ERCC1</italic> rs3212986 show decreased risk of grade 3-4 hematologic toxicity in two studies. These two SNPs may be important molecular biomarkers for predicting platinum-induced hematological toxicities. <italic>XRCC1</italic> rs25487 (G23885A, Arg399Gln) show positive association in six studies, emphasizing the potential contribution of BER pathway in oxidative stress in platinum-induced hematological toxicity, since cisplatin can exert cytotoxic effects through the generation of ROS (<xref ref-type="bibr" rid="B143">Zheng et al., 2020</xref>).</p>
<p>Apart from that, lots of genetic variants located in genes not directly linked to drug exposure are investigated. The GWAS have identified a handful of candidate genetic variants associated with platinum-based hematological toxicities and novel biologic pathways of potential impact. But these studies still face the challenge of statistically underpowered and stringent threshold of multiple testing. Additional validation in multiple independent sample sets or functional analyses are required to further elucidate the gene-phenotype relationship (<xref ref-type="bibr" rid="B75">Low et al., 2014</xref>).</p>
</sec>
<sec id="s4-2">
<title>4.2 Quality and inconsistency among studies</title>
<p>Genetic association studies require a large number of patients to provide adequate power, as a rare variant with large effect, or common variant with modest effect is more probable in genetic epidemiology (<xref ref-type="bibr" rid="B9">Campbell et al., 1995</xref>). While the majority of the studies in our systematic review did not indicate the sample size calculation in their statistical analysis, and the sample size in most studies in our systematic review are much smaller than that would be implied, which may be underpowered to detect a statistically significant relationship (<xref ref-type="bibr" rid="B54">Jorgensen and Williamson, 2008</xref>).</p>
<p>One of the challenges in pharmacogenomics is the ethnic background of the study population. The prevalence of toxicity varies according to the ethnic background (<xref ref-type="bibr" rid="B86">O&#x2019;Donnell and Dolan, 2009</xref>; <xref ref-type="bibr" rid="B67">Li and Meyre, 2013</xref>). For example, higher rates of toxicities have been observed in east Asian populations compared to European and North American populations (<xref ref-type="bibr" rid="B124">Watanabe et al., 2003</xref>). In addition, allele frequency of genetic variants vary depending on the ethnic background or even the geographical location. When cases and controls are drawn from multiple ethnic or geographic groups, population stratification exists, which may put the study at risk of confounding and can lead to false positive associations (<xref ref-type="bibr" rid="B54">Jorgensen and Williamson, 2008</xref>). Population stratification was seldom assessed in most genetic association studies, which has been cited as a major reason for lack of replication.</p>
<p>Different treatment protocols are recommended according to cancer types. The composition, proportion and cycles of chemotherapy regimen can influence the incidence and degree of hematological toxicity. Furthermore, treatment protocols may also differ with regard to the use of concomitant supportive treatments. The time and dose of granulocyte colony-stimulating factor administered may be various across institutions, which are seldom mentioned in the method part and may bring confounds in genetic association studies. Moreover, there are overlap in metabolic pathway between platinum and other antineoplastic drugs, which can alter the pharmacogenetic effects of polymorphisms. For example, The ABC transporter ABCB1 and ABCC2 is responsible for the efflux of many commonly used antineoplastic drugs that usually used in combination with platinum agents, including taxanes (<xref ref-type="bibr" rid="B78">Marsh, 2006</xref>; <xref ref-type="bibr" rid="B63">Lambrechts et al., 2015</xref>). If Pt-DNA lesions are not repaired, the DNA lesion triggers activation of the apoptosis pathway, an essential step for the effectiveness of platinum-based chemotherapeutics for killing tumor cells, which is also the apoptosis pathway of many other cytotoxic drugs (<xref ref-type="bibr" rid="B32">Fulda and Debatin, 2006</xref>). Apart from the role of participating in DNA synthesis, MTHFR encode key enzymes for the metabolism of 5-FU (<xref ref-type="bibr" rid="B65">Lee et al., 2013</xref>) and RRM1 was also the primary target for gemcitabine (<xref ref-type="bibr" rid="B137">Yuan et al., 2015</xref>).</p>
<p>Genetic association studies are heavily reliant on the phenotype, but it may be difficult to establish the true phenotype. Although myelosuppression is quantitative, the degree of myelosuppression could be missed based on the frequency of measurement. Apart from that, differences in the toxicity assessment criterion and endpoints may hamper reproducibility of previous findings. Some studies analyzed the total hematological toxicity (<xref ref-type="bibr" rid="B123">Wang et al., 2008</xref>; <xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>; <xref ref-type="bibr" rid="B41">Gu et al., 2012</xref>), while other studies analyzed the detail hematological toxicity (leukopenia, neutropenia, thrombocytopenia or anemia) (<xref ref-type="bibr" rid="B50">Isla et al., 2004</xref>; <xref ref-type="bibr" rid="B113">Tibaldi et al., 2008</xref>; <xref ref-type="bibr" rid="B131">Xu et al., 2012</xref>). The detail hematological toxicity may be more accurate and clinically relevant, but its low incidence requires cohort study with large sample size, which are unattainable in the current researches. Furthermore, methodological flaws were observed in the imprecise dichotomization of patients with mild toxicity and severe toxicity. The majority use the occurrence of grade 3-4 as endpoints, other studies use grade 2-4 (<xref ref-type="bibr" rid="B50">Isla et al., 2004</xref>; <xref ref-type="bibr" rid="B27">Er&#x10d;ulj et al., 2012</xref>; <xref ref-type="bibr" rid="B49">Huang et al., 2015</xref>; <xref ref-type="bibr" rid="B53">Jia et al., 2016</xref>; <xref ref-type="bibr" rid="B70">Liblab et al., 2020</xref>) or grade 1-4 (<xref ref-type="bibr" rid="B15">Chen et al., 2010</xref>; <xref ref-type="bibr" rid="B27">Er&#x10d;ulj et al., 2012</xref>; <xref ref-type="bibr" rid="B23">Deng et al., 2015</xref>; <xref ref-type="bibr" rid="B117">Walia et al., 2022</xref>). Medical interventions of dose reduction and/or treatment discontinuation were taken when grade 3-4 hematological toxicity arises. Therefore, the toxicity endpoints of grade 2-4 or grade 1-4 may not be clinically relevant (<xref ref-type="sec" rid="s11">Supplementary Table S4</xref>).</p>
<p>There is statistical heterogeneity in the data analysis (<xref ref-type="sec" rid="s11">Supplementary Table S5</xref>). Some studies just used chi-square test or fisher&#x2019;s exact test to estimate the difference of genotype distribution in cases and controls (<xref ref-type="bibr" rid="B61">Kimcurran et al., 2011</xref>; <xref ref-type="bibr" rid="B55">Kalikaki et al., 2015</xref>). Others use logistic regression to make comparisons between groups and generate odds ratios and 95% confidence intervals. Logistic regression is more appropriate as it can provide a quantitative measure of the relationship between the groups, allow adjustment for confounding factors, and detect gene-gene or gene-environment interactions. Some studies made a clear statement about mode of inheritance assumed for analysis, and used more than one assumption (<xref ref-type="bibr" rid="B92">Peng et al., 2014</xref>; <xref ref-type="bibr" rid="B7">Bushra et al., 2020</xref>; <xref ref-type="bibr" rid="B30">Ferracini et al., 2021</xref>; <xref ref-type="bibr" rid="B117">Walia et al., 2022</xref>), while other studies only compared the three categories of genotype frequencies (homozygous wild type, heterozygous, homozygous variant) between cases and controls (<xref ref-type="bibr" rid="B50">Isla et al., 2004</xref>; <xref ref-type="bibr" rid="B44">Han et al., 2007</xref>; <xref ref-type="bibr" rid="B58">Kim et al., 2009</xref>; <xref ref-type="bibr" rid="B65">Lee et al., 2013</xref>; <xref ref-type="bibr" rid="B70">Liblab et al., 2020</xref>). 30 of the included studies performed the correction for multiple comparisons and only 10 studies performed validation of the results or by splitting the cohort for a primary and an exploratory analysis (<xref ref-type="bibr" rid="B79">Marsh et al., 2007</xref>; <xref ref-type="bibr" rid="B96">Qian et al., 2012</xref>; <xref ref-type="bibr" rid="B10">Cao et al., 2016</xref>; <xref ref-type="bibr" rid="B40">Gr&#xe9;en et al., 2016</xref>; <xref ref-type="bibr" rid="B53">Jia et al., 2016</xref>; <xref ref-type="bibr" rid="B133">Yin et al., 2016</xref>; <xref ref-type="bibr" rid="B144">Zheng et al., 2017</xref>; <xref ref-type="bibr" rid="B4">Bj&#xf6;rn et al., 2020a</xref>; <xref ref-type="bibr" rid="B3">Bj&#xf6;rn et al., 2020b</xref>; <xref ref-type="bibr" rid="B110">Svedberg et al., 2020</xref>).</p>
</sec>
<sec id="s4-3">
<title>4.3 Limitations</title>
<p>This review has several limitations, which mainly reflects the status of current genetic association studies. In the search process, many studies had to be excluded because hematological toxicity was not clearly described or there is no toxicity grading criterion. What&#x2019;s more, we observed that the most studies did not provide toxicity statistics data (no <italic>p</italic>-value) or just provide insufficient toxicity data (for example, some studies only mentioned correlation in the results section without providing the original statistical data), which may raise some doubts of data authenticity. Also, some studies did not control exclusion criteria of prior history of chemotherapy and/or radiation or a considerable proportion of the patients receive chemotherapy combined with radiation or other non-platinum chemotherapy regimens, which may increase the likelihood of cumulative hematological toxicity. There is much heterogeneity between incorporated studies, thus we were unable to perform a quantitative comparison and meta-analysis.</p>
</sec>
<sec id="s4-4">
<title>4.4 Implications for clinical practice and research</title>
<p>Future studies should focus on the following aspects. Firstly, genetic association study inevitably faces the concerns of bias and confounding, and are susceptible to inappropriate conclusions, therefore it calls for careful planning of study design to improving quality of methodology (<xref ref-type="bibr" rid="B102">Saito et al., 2006</xref>). Secondly, the majority genetic polymorphisms identified in the eligible publications were repeated in only one or two studies (<xref ref-type="bibr" rid="B46">Hilary et al., 2024</xref>). SNPs screened out as potential factors in susceptibility to hematological toxicity in our systematic review require well-planned, methodologically robust studies to validate them. Thirdly, functional predictions of significant genetic variants needed to be confirmed and validated <italic>in vitro</italic> or <italic>in vivo</italic> work (<xref ref-type="bibr" rid="B29">Felipe Antonio de Oliveira et al., 2022</xref>). Fourthly, more studies should emphasize on the hematopoiesis-related pathways identified in a whole-exome sequenced study of 215 NSCLC patients treated with a single treatment (<xref ref-type="bibr" rid="B4">Bj&#xf6;rn et al., 2020a</xref>). Moreover, clinical trial with large sample size to perform subgroup analysis should be conducted to allow proper stratified analysis. Finally, owing to the complexity of mechanisms of platinum action, a single SNP alone may have low effect to platinum response, thus supporting a polygenetic effect in platinum&#x2010;induced hematological toxicity (<xref ref-type="bibr" rid="B20">Daniel et al., 2023</xref>). Future direction should be establishing appropriate statistical methods with capacity to integrate multiple genetic, phenotypic, epidemiological and clinical variables effects.</p>
</sec>
</sec>
<sec sec-type="conclusion" id="s5">
<title>5 Conclusion</title>
<p>To summarize, this systematic review has successfully reported and evaluated studies on genetic associations of platinum-based hematological toxicities. Review of these studies identified several genetic variants that potentially affect the risk of platinum-induced hematological toxicity. Many methodological issues exist that may affect reproducibility of results and lead to inconsistency, including insufficient sample size, population stratification, various treatment schedule, heterogeneity in the assessment of hematological toxicity and statistics. Well-designed studies with sufficient samples sizes and standardization of phenotypes are warranted to address the limitations of the current studies and to ensure the robust findings that can be more effective to be used in personalized therapeutics.</p>
</sec>
</body>
<back>
<sec sec-type="data-availability" id="s6">
<title>Data availability statement</title>
<p>The original contributions presented in the study are included in the article/<xref ref-type="sec" rid="s11">Supplementary Material</xref>, further inquiries can be directed to the corresponding authors.</p>
</sec>
<sec id="s7">
<title>Author contributions</title>
<p>YZ: Conceptualization, Formal Analysis, Methodology, Supervision, Writing&#x2013;original draft. MT: Conceptualization, Formal Analysis, Methodology, Writing&#x2013;review and editing. ZD: Conceptualization, Formal Analysis, Methodology, Writing&#x2013;review and editing. PC: Conceptualization, Formal Analysis, Writing&#x2013;review and editing.</p>
</sec>
<sec sec-type="funding-information" id="s8">
<title>Funding</title>
<p>The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by Health Research Project of Hunan Provincial Health Commission (D202302046032, W20243057), National Key Clinical Specialty Scientific Research Project (Z2023110), as well as National Natural Science Foundation of China (81903111).</p>
</sec>
<sec sec-type="COI-statement" id="s9">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec sec-type="disclaimer" id="s10">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
<sec id="s11">
<title>Supplementary material</title>
<p>The Supplementary Material for this article can be found online at: <ext-link ext-link-type="uri" xlink:href="https://www.frontiersin.org/articles/10.3389/fphar.2024.1445328/full#supplementary-material">https://www.frontiersin.org/articles/10.3389/fphar.2024.1445328/full&#x23;supplementary-material</ext-link>
</p>
<supplementary-material xlink:href="Table1.docx" id="SM1" mimetype="application/docx" xmlns:xlink="http://www.w3.org/1999/xlink"/>
<supplementary-material xlink:href="Table8.docx" id="SM2" mimetype="application/docx" xmlns:xlink="http://www.w3.org/1999/xlink"/>
<supplementary-material xlink:href="Table7.docx" id="SM3" mimetype="application/docx" xmlns:xlink="http://www.w3.org/1999/xlink"/>
<supplementary-material xlink:href="Table2.DOCX" id="SM4" mimetype="application/DOCX" xmlns:xlink="http://www.w3.org/1999/xlink"/>
<supplementary-material xlink:href="Table5.docx" id="SM5" mimetype="application/docx" xmlns:xlink="http://www.w3.org/1999/xlink"/>
<supplementary-material xlink:href="Table3.DOCX" id="SM6" mimetype="application/DOCX" xmlns:xlink="http://www.w3.org/1999/xlink"/>
<supplementary-material xlink:href="Table4.docx" id="SM7" mimetype="application/docx" xmlns:xlink="http://www.w3.org/1999/xlink"/>
<supplementary-material xlink:href="Table6.docx" id="SM8" mimetype="application/docx" xmlns:xlink="http://www.w3.org/1999/xlink"/>
</sec>
<sec id="s12">
<title>Abbreviations</title>
<p>AUC, area under curve; BER, base excision repair; CI, confidence interval; DSB, double-strand break repair; FA, fanconi anemia; FOLFOX, oxaliplatin, leucovorin and 5-fluorouracil; FR, flanking region; GWAS, genome-wide association studies; HR, homologous recombination; ICL, interstrand crosslink; MMR, mismatch repair; NCI-CTCAE, National Cancer Institute-Common Terminology Criteria for Adverse Events; NSCLC, non-small cell lung cancer; NER, nucleotide excision repair; OR, odds ratios; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; ROS, reactive oxygen species; SNP, single nucleotide polymorphism; TLS, translesion DNA synthesis; UTR, untranslated region; WHO, World Health Organization.</p>
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