A Review of Cancer Genetics and Genomics Studies in Africa

Cancer is the second leading cause of death globally and is projected to overtake infectious disease as the leading cause of mortality in Africa within the next two decades. Cancer is a group of genomic diseases that presents with intra- and inter-population unique phenotypes, with Black populations having the burden of morbidity and mortality for most types. At large, the prevention and treatment of cancers have been propelled by the understanding of the genetic make-up of the disease of mostly non-African populations. By the same token, there is a wide knowledge gap in understanding the underlying genetic causes of, and genomic alterations associated with, cancer among black Africans. Accordingly, we performed a review of the literature to survey existing studies on cancer genetics/genomics and curated findings pertaining to publications across multiple cancer types conducted on African populations. We used PubMed MeSH terms to retrieve the relevant publications from 1990 to December 2019. The metadata of these publications were extracted using R text mining packages: RISmed and Pubmed.mineR. The data showed that only 0.329% of cancer publications globally were on Africa, and only 0.016% were on cancer genetics/genomics from Africa. Although the most prevalent cancers in Africa are cancers of the breast, cervix, uterus, and prostate, publications representing breast, colorectal, liver, and blood cancers were the most frequent in our review. The most frequently reported cancer genes were BRCA1, BRCA2, and TP53. Next, the genes reported in the reviewed publications’ abstracts were extracted and annotated into three gene ontology classes. Genes in the cellular component class were mostly associated with cell part and organelle part, while those in biological process and molecular function classes were mainly associated with cell process, biological regulation, and binding, and catalytic activity, respectively. Overall, this review highlights the paucity of research on cancer genomics on African populations, identified gaps, and discussed the need for concerted efforts to encourage more research on cancer genomics in Africa.


INTRODUCTION METHODS
The peer-reviewed publications included in this review were extracted from PubMed and covered the period between January 1990 and December 2019, as shown in the flow chart in Figure 1. Since PubMed Medical Subject Heading (MeSH) terms involve synonym control, it yields more precise and inclusive search results (16). Our literature search approach, therefore, utilized an integration of MeSH terms that incorporated "the disease" (neoplasm), 54 African countries, and combinations of study parameters ('gene or protein or molecular biology or mutation or genetics or genomics'). After extracting African cancer papers, we next filtered those to include only papers pertaining to cancer molecular biology (protein or nucleic acid). Cancer molecular biology papers were then further filtered using "genetic* OR genomic* OR mutation*[MeSH Terms]." The final criteria were that the studies must utilize biospecimens of African origin. Two authors (SOR and OAR) manually verified these publications to ensure the accuracy of terms.
For the purpose of data extraction, the metadata and abstract of each publication returned from our search were collected in a single corpus and subjected to text-mining using the R packages RISmed (17) and Pubmed.mineR (18). The publications returned were analyzed in R to identify the cancer types/sites associated with each publication, as described by Acharya et al. (19). Furthermore, the R package "PubmedmineR" was used for obtaining the names and frequency of occurrence of genes denoted in "Human Genome Nomenclature Committee" (HGNC) symbols (20). For this purpose, we considered the genes reported in the abstract as the genes associated with the most prominent findings of the publications. Next, these genes were pulled and subjected to gene ontology functional profiling for three gene ontology classes ("molecular function", "biological process", and "cellular component") using "goProfiles" (21). critical cancer-associated genes. Next, we reviewed some of the key findings reported across the 375 genomics papers for each of the major and most frequently published cancer types below.

Breast/Ovarian Cancer
Breast cancer has continued to be the leading cause of cancer morbidity and mortality in Africa, with an incidence and mortality rate of 37.9 and 17.2 per 100000, respectively, according to GLOBOCAN 2018 data (2). Breast cancer's prominence in Africa dates back to around 3000BC in the ancient Egyptian medical text -the Edwin Smith Papyrus, the oldest cancer record (23, 24). Not surprisingly, breast cancer had the highest number (n=82, 19%) of peer-reviewed cancer genetics/genomics publications in Africa. With the current understanding of cancer as a genomic disease and the unique phenotype that breast cancer presents in the people of African ancestry, attempts to address its burden require rigorous genomics investigations.
Together with cancer of the ovary, breast cancer risk is greatly increased in women with inherited mutation(s) in tumor suppressor genes (25). Not surprisingly, the earliest publications on breast and ovarian cancers in African populations focused on understanding the contribution of variations in the tumor suppressor genes BRCA1/2 and TP53, particularly in North African populations of Morocco, Tunisia, Egypt, and Sudan (26-40). While these findings hold immense benefits for those populations, their BRCA variants are not dissimilar to those present in the out-of-Africa populations. This, therefore, limits the translational impact of such findings to controlling breast/ovarian cancer in the Sub-Saharan African populations. Furthermore, the major epidemiological implication of BRCA mutations lies in identifying specific founder mutation(s) within each population, with the view of using it as a predictive molecular risk marker and treatment recommendation. For instance, advances in understanding the role of BRCA proteins in tumorigenesis have now led to improved therapeutic choices with the availability of PARP inhibitors for breast cancer patients with germline mutations (41). Also, the identification of founder BRCA gene mutations in populations like Ashkenazi-Jewish (Hungarian and Russian), Polish, Norwegian and Icelandic people has resulted in improved low-cost genetic testing and the determination of high-risk individuals for breast and ovarian cancers (42, 43). Therefore, these have made it imperative for the founder mutations of the BRCA gene within Africa populations to be identified and included in breast cancer screening, diagnosis, and treatment.
In an attempt to consider BRCA contributions to breast cancer in Africa, Rebbeck et al. (44) published a global distribution of BRCA1 and BRCA2 germline mutations by including women from Nigeria and South Africa. However, the extent to which their subjects represent the ethnic and genetic diversity in these countries is unclear. They did note that the mutations observed in African American families were of African origin because they are unlike the mutations seen in out-of-African ethnic groups (44-46). This study of Rebbeck et al. (44)  Recently, Mahfoudh et al. (51) showed that the 5382insC BRCA1 mutation contributes to the development of triplenegative breast cancer (TNBC) in Tunisia. The higher mortality of breast cancer in women of West African ancestry is due in part to higher levels of TNBC (compared to whites), which is associated with the poorest prognosis of all breast cancer subtypes. Hence, BRCA screening in Africa could help identify women who can benefit from PARP inhibitors leading to improved clinical outcomes. In South Africa, Reeves et al. (52) characterized BRCA1 mutations in breast and/or ovarian cancer to identify founder mutations in Afrikaner families. However, this population is also of European ancestry, and the mutations that were identified were similar to those reported in the Netherlands and in Ashkenazi Jews (53). They also reported that variants of PALB2, a partner and localizer of BRCA2 was also associated with the early onset of breast cancer in some South African patients (53). PALB2 functions as a scaffold between BRCA1 and BRCA2. Similar PALB2 mutations have previously been identified in women of European ancestry but not in women with Nigerian ancestry, as reported by Sluiter et al. (54).
The first publication on BRCA mutations in the indigenous Sub-Saharan African population was by Zhang et al. (55), who identified an ancient BRCA1 mutation (Y101X) in Yoruba (Nigeria, West Africa) breast cancer patients. The team further reported a non-pathogenic novel exon 21 deletion of BRCA1 (c. 5277 + 480_5332+672del) in Nigeria in addition to a novel deleterious BRCA1 mutation (c. 1949_1950delTA) in a woman from Senegal (West Africa) (56). Another novel founder, BRCA2  (95). Other DNA repair genes that have been studied in Africa include XRCC1 and XPD in Egypt (96,97). Overall, even though it is one of the most studied genes in African cancer research, there remains a very small number of publications on BRCA mutations in the indigenous African population, clearly showing a knowledge gap on a hereditary gene critical in managing incidence and clinical outcomes in breast cancer.
Exogenous factors that drive DNA damage include viruses and xenobiotics. The presence of these agents and genetic alterations that mediate the ensuing host-response can promote carcinogenesis. The first reports of virus-associated breast cancer in Africa were by Levine et al. (98) and Hachana et al. (99), who reported the presence of a human breast carcinoma virus (a virus similar to mouse mammary tumor virus) in 74% of tumors in Tunisia. These were the only two studies that reported this virus in Africa. Studies have also shown an association of the hepatitis C virus in Egypt (100) and Human papillomavirus (HPV) in Rwanda (101) to breast cancer progression. However, the most reported virus linked to breast cancer in Africa is the Epstein-Barr virus (EBV), with studies published in Algeria (102), Eritrea (103), Egypt (104), and Sudan (105). EBV was the first identified human oncogenic virus that was detected in Uganda in 1964 by Denis Parsons Burkitt (106-108) and its molecular pathogenesis has been reviewed by Lawson et al. (109). The virus is responsible for many cancers across the continent, and the host genomic factors that facilitate tumorigenesis are described below.
The detoxification of carcinogenic chemical entities is primarily catalyzed by cytochrome P450 (phase I) and a host of phase II xenobiotic-metabolizing enzymes. Polymorphisms in these genes dictate, in large part, the effect of xenobiotics on the biological system. Such polymorphisms have been reported in CYP1A1 and CYP1B1 in Nigeria and Egypt (110,111), CYP2D6 in South Africa (112), and CYP1A2 in Tunisia (113). Furthermore, as hormone-responsive cancers, these cytochrome P450 genes play critical roles in estrogen metabolism and the response of the tumor to endocrine therapy. For genes coding for phase II xenobiotics metabolizing enzymes, the deletion of GSTT1 and GSTM1 were reported by Khedhaier (114) to predict the early onset and prognosis of breast cancer among Tunisian women. The number of TA repeats in the promoter of low activity UGT1A1 was reported to be protective against breast cancer in pre-menopausal Nigerian women (115,116). Similarly, the association of polymorphisms in paraoxonase, cyclooxygenase, glyoxalase, and glutathione peroxidase genes with breast cancer were reported in Egypt and Rwanda (117)(118)(119)(120).
Inflammation is a major hallmark of cancer, and it is known to contribute to aggressive tumor biology. This makes understanding the variations in immuno-oncogenic genes important in understanding the population biology of cancer in Africa. Mestiri et al. (121,122) reported that polymorphisms in TNF-a and TNFRII increase the susceptibility to breast cancer in Tunisian women, with TNFRII -196R prevalent in premenopausal women. Conversely, FASL (rs763110) was associated with a good prognosis in the same population (123). However, HLA-DQB1 and HLA-G +3142C>G (rs1063320) polymorphisms were related to increased breast cancer susceptibility (124,125). Pathogenic polymorphisms of other inflammatory genes like NRF2, IL1a, IL1b, IL6, IL8, and CXCR2 have also been identified in Tunisian and Egyptian breast cancer patients (126)(127)(128)(129)(130).
Recent evidence suggests that inflammation-driven cancer in Blacks is influenced by vitamin D levels (131, 132). To establish the association of vitamin D variants and related genes with breast cancer, El-Shorbagy et al. (133), Abd-Elsala et al. (134) and Shaker & Senousy (135) showed that polymorphisms in the vitamin D receptor (VDR) increases the risk of breast cancer in Egyptian women who carry the ATT haplotype. The risk of developing breast cancer due to these mutations was elevated in women who also carry RANKL (rs9533156), OPG (rs2073617), and CHI3L1 (rs4950928) (135). Similar studies have also reported the risk allele in Ethiopian women as VDR rs2228570 (FokI) (136) but the study of Wang et al. (137) did not identify variants in vitamin D related genes as risk factors for breast cancer in Nigerian women that were used as the ancestral population for African American women. This genome-wide association study, however, identified TYRP1 (rs41302073), a melanin synthesis regulatory gene, as a significant risk allele for breast cancer in their dataset that included African American and Barbadian women. Furthermore, the authors also used the same dataset to identify WWCI as an important susceptibility locus in the Hippo pathway for breast cancer (138).
Polymorphisms in the angiogenesis-associated genes have also been identified in breast cancer in African populations and include the LEP, LEPR, VEGF, and MMP2. Leptin and LEPR Q223R (rs1137101) were identified as risk factors for breast cancer in Egyptian and Nigerian women (139-141) while leptin alone was notably reported as a key driver of breast cancer progression through the induction of JAK/STAT3, ERK1/ 2, and estrogen pathways in obese Egyptian women (142). Furthermore, variants of VEGF and MMPs, which induce the upregulation of these proteins, were reported as risk factors in North African countries of Morocco, Egypt, and Tunisia (143-148). Other overexpressed angiogenic proteins reported are EGFR in Tunisia (149) and IGFBP2 and IGFBP5 in Nigerian women (150). The authors proposed these angiogenic proteins as druggable targets in breast cancer treatment. Another therapeutic pathway that has been studied is the PIK3/AKT pathway. Jouali et al.
(151) reported PIK3CA hotspot mutations in 13% of triple-negative breast cancer cases in Morocco. They suggested that this pathway could be of therapeutic importance for triple-negative breast cancer in Morocco.
Cancer is a polygenic disease, and scientific investigation to understand breast cancer's population biology, therefore, cannot be simplified to a single genetic variant. Hence, techniques to investigate multiple genes at a time such as with next generation sequencing are now being utilized to understand the genetic risk factors of breast cancer in Africa. To that effect, genome-wide studies ( , and RCC1 in BRCA1/2 mutation-negative patients with familial breast cancer. A similar study in Egypt also found other novel genetic variants responsible for familial breast cancer. These genetic variants are different from those linked to DNA damage repair (like BRCA1 and BRCA2) but are linked to other functional genes like NBPF10, ZNF750, CHTI5, NPIPB11, and PHIP, that are involved in RNA binding, transcriptional regulation, extracellular matrix, a structural protein, and signal transduction, respectively.
The contribution of epigenetic factors to risk and prognosis of breast cancer reported in Africa included the roles of tissue microRNA, circulating free mRNA, circulating long non-coding RNA (158-163) as well as DNA methylation status of breast cancer susceptibility genes like APC, ERa, RASSFIA, UCHL1, COX-2, and FHIT (161, 164-167) in breast tumor across Africa.

Prostate Cancer
Prostate cancer continues to be the leading cause of cancer morbidity and mortality among African men (168,169). Although genetics is a major risk factor for this disease, there are only a few publications on prostate cancer genomics in Africa. In this subsection, we review 14 papers that were relevant to prostate cancer out of the list of 375 papers extracted. Prostate cancer presents with an aggressive phenotype among men of African descent, and like breast cancer, it is a hormoneresponsive tumor. Consequently, early studies on this disease identified androgen's influence in the control of normal prostate growth and, in its transformation into adenocarcinoma, a phenomenon called the "androgen hypothesis" (170,171). Therefore, peer-reviewed publications on prostate cancer genetics in African populations have reported genetic variants that contribute to elevated circulating androgens, including androgen reduced clearance and upregulated activity of androgen receptor. These include the polymorphisms in cytochrome P450 genes like CYP3A4, CYP3A5, CYP1A1, CYP17 in Morocco, Tunisia, Nigeria, South Africa, and Senegal (172)(173)(174)(175)(176). Besides, alterations in CAG and GGN repeats in the androgen receptor gene have been reported as risk factors in North Africa, Ivory Coast, and Nigeria (177,178). Unlike the North African populations, prostate cancer in Sub-Saharan African populations and North African Berbers were associated with high frequencies of low size alleles (CAG under 18 repeats, and GGC under 15 repeats) (178). Other reported genetic variations that increase African populations' susceptibility to prostate cancer include GSTM1, GSTT1, UDPglucuronosyltransferase, and sulfotransferase in Tunisia and Algeria (179)(180)(181)(182).
A deeper understanding of the disease's polygenic risk was elucidated by four studies that have investigated the genomewide genetic variations in prostate cancer across Africa. These included GWAS of prostate cancer in Tunisia, Ghana, and Uganda (183)(184)(185), as well as a whole-genome sequencing of six individuals in South Africa (186). It is interesting to note that these four studies did not identify any common high-risk prostate cancer variants. The Tunisian study identified three regions (on chromosomes 9, 17, and 22) containing 14 significant SNPs, three of which are shared with Caucasian populations (185). The Ghanaian study of Cook et al. (184) identified 30 most significant SNPs distributed across chromosomes 1, 2, 3, 5, 6, 7, 8, 9, 10, 13, and 20.
Meanwhile, the Ugandan study identified risk alleles on chromosomes 1, 6, 11, 13, 14, and 17 (183). Although the Ugandan and Ghanaian populations shared cytoband 6p21.32 in common, the nucleotide positions and risk alleles were still different. This chromosome position codes for HLA-DQB1, which has been reported to be important for the adaptation of African ancestral populations to the African rainforest environment. These studies further add to the existing evidence of the heterogeneity of African populations (12) and that cancers in these populations may have a different biology. These findings provide further evidence for the need to disaggregate the Black population by genetic lineage in studying the contributions of genomics to racial disparities of diseases like prostate cancer. Importantly, it is yet to be revealed whether these differences influence the disease phenotype and disparity in outcome.
The most commonly reported genomic alteration that drives prostate tumorigenesis is TMRPSS2-ERG fusion, and this androgen-upregulating fusion is known to correlate with higher grades of the disease. Although men of African ancestry are known to present with higher disease grade, only three studies have examined the TMRPSS2-ERG fusion on the Continent (187)(188)(189). This fusion often results from either a chromosomal translocation or an interstitial deletion, and these studies reported rates that were less than 20% in Ghanaian and Black South African patients (187)(188)(189).

Liver Cancer
According to the 2018 GLOBOCAN data, hepatocellular carcinoma accounted for 8.4 cases per 100,000 and 8.3 deaths per 100,000 globally (2) and it is the 4 th most common cancer in Africa. We retrieved 46 publications that studied liver cancer genetics/genomics in Africa. Several of these studies investigated the contribution of the hepatitis virus and mycotoxins to this malignancy. These biotic and abiotic agents represent the major causes of this disease on the continent (190,191). Hence, a preponderance of publications on liver cancer in Africa focused on understanding the contribution of mutation and expression of TP53, and other tumor suppressors like TP73, RB, KLF6, and CTNNB1, to liver carcinogenesis (190,(192)(193)(194)(195)(196)(197)(198)(199)(200)(201)(202)(203)(204)(205)(206)(207), particularly in Senegal, Gambia, Nigeria, South Africa, Egypt, and Morocco. These studies identified the mutation in codon 249 of TP53 as a genetic risk factor for developing hepatocellular carcinoma following exposure to either the hepatitis virus or mycotoxins (see Lin et al. (208) for detailed mechanism). In Morocco, MDM2 309 T>G was associated with liver cancer (209,210). These mutations are known to upregulate this oncogene's expression, which in turn binds p53 and prevents its tumor suppression function (209) resulting in increased genomic instability as demonstrated by loss of heterozygosity in chromosome 4-q13 in Black South Africans (211).
The development of hepatocellular carcinoma is often preceded by chronic inflammation of the liver. In Africa, hepatic inflammation is exacerbated by high-prevent comorbid conditions like non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and liver cirrhosiss. For instance, the prevalence of NAFLD in Nigeria, Ethiopia, and South Africa has been reported to be 68.8%, 73%, and 87%, respectively (212).
Other authors have focused on the development of biomarkers for liver cancer, using epigenetic factors like microRNAs. These include serum Mir-224, Mir-215, Mir-143, Mir-122, Mir-199a, and Mir-16 (220,221). Specifically, Mir-122 and Mir-222 levels were reported by Motawi et al. (222) as a discriminating biomarker for distinguishing liver injury from liver cancer. This group further reported that LncRNA HULC rs7763881 and MALAT rs619586 were associated with decreased susceptibility of Egyptian hepatitis virus-persistent carriers to liver cancer (223).
Mycotoxicosis, with concomitant early-life protein malnutrition, is an important driver of liver cancer in Africa (224)(225)(226). One group of enzymes that are involved in detoxifying mycotoxins are the glutathione-S-transferases (m, q, p, a, s). Hence, individuals who do not express all the enzymes due to homozygous deletion are more susceptible to myco-carcinogens (227). Overall, two studies have identified the deletion of GSTM1 and GSTT1 haplotypes as risk factors for aflatoxin-associated hepatocellular carcinoma (228,229) in Africa.
The last group of genes that have been studied on hepatocellular carcinoma in Africa are those involved in angiogenesis, including VEGF, MMP, RASSF1A, and RECK. In Egypt, Samamoudy et al. (230) reported that patients with MMP9 (rs3918242) are at high risk of developing liver cancer while RECK (rs12814325) (231) could account for the disease progression and metastasis.

Cervical Cancer
Cervical cancer continues to be responsible for the highest cancer mortality in Africa, accounting for 2,000,000 deaths in 2018 (2), and its incidence rates continue to increase in most Sub-Saharan African countries (232). However, studies on cervical cancer genetics/genomics only represented 3% of the publications we retrieved. Similar to liver cancer, cervical cancer is viral-related and primarily caused by Human Papillomavirus (HPV). Several reviews have discussed the burden, distribution, and contribution of HPV serotypes to cervical cancer in Africa (233)(234)(235). Despite the burden of HPV in Africa, only a small proportion of women that are infected develop cervical cancer (236,237). It is, therefore, essential to understand the genetic factors that contribute to the risk of progression from HPV infection to cervical cancer across Africa.
One of such genetic factors that increase susceptibility to HPV-associated cervical carcinogenesis is the TP53 R72P mutation (238), which was reported in Gabon, Senegal, Sudan, Morocco, and South Africa; and this risk increases when combined with the chromosomal allelic loss of RB or with aberrant methylation of DAPK1, RARB, TWIST1, and CDH13 (79, [239][240][241][242][243][244]. Furthermore, aberrant methylation of these genes was proposed by Feng et al. (245) to be useful in Senegal for the screening of cervical cancer, either alone or in combination with cytology. The importance of this homozygous arginine polymorphism at codon 72 of TP53 in determining genetic susceptibility of a population has been shown in Israeli Jewish women who have been reported to have reduced susceptibility to HPV-associated cervical cancer (246).
The variations in genes involved in inflammatory and apoptotic response pathways have also been reported to increase African women's susceptibility to cervical cancer (247). The reported polymorphisms in Africa include those of TLR 2/3/4/9 and IL1/10/15 genes in Tunisia and -308 promoter polymorphism of TNF-a in South Africa (248)(249)(250). Meanwhile, polymorphisms in FASR-670A and CASP8-652 were associated with a reduced risk of developing cervical cancer in South African women (251).

Colorectal Cancer
Colorectal cancer is the 5 th most common cancer in Africa and accounted for 550,000 deaths in 2018 (2). We retrieved 56 publications on colorectal cancer genetics/genomics from Nigeria, Ghana, South Africa, Algeria, Tunisia, Morocco, and Egypt. The findings in these publications included: (1) (259,271,274,(276)(277)(278)(279)(280)(281). Other studies have also explored the contribution of epigenetic changes to colorectal cancer carcinogenesis in Africa (278,(282)(283)(284)(285). For example, the methylation of UCH1 and p14ARF genes were reported to drive colorectal cancer in the presence of TP53 mutation in Tunisia (282,283,286,287). Other studies on the North African populations reported the influence of polymorphisms in telomere and mitochondrial D-loop region on the clinicopathological characteristics of the colorectal cancers among their patients (288,289). Hence, the dearth of data on the genomics of this disease makes it difficult to explain the increase in the level of sporadic colorectal cancers reported in African countries, despite the difference in lifestyle and dietary habits. Profiling of these genes, including the use of targeted next-generation sequencing, in the screening and clinical management of this disease is essential in reducing its burden (255, 290).

Lung Cancer
Across Africa, lung cancer ranks 6 th, with about 550,000 cases in 2018 (2). However, the burden of this disease is on the North African countries and South Africa (2). This burden reflects the pattern of tobacco smoking reported through national surveys (291). Lung cancer genetics/genomics studies have also largely been conducted on the North African populations of Tunisia and Egypt. These studies investigated the role of angiogenic pathway genes like EGFR and MMP-3 in lung carcinogenesis (292)(293)(294)(295)(296)(297). The expression of EGFR was associated with poor prognosis, and the frequency of the mutations observed in Tunisian and Moroccan patients was similar to those of Europeans (294,296,298). However, Dhieh et al. (292) found that abnormal p53 expression in these patient populations was more frequent than in Europeans. Similarly, a nonsense mutation (Arg-196-Term) in exon 6 of TP53 was identified in the small cell lung cancer from gold miners in South Africa (299).
There were additional studies that used epigenetic techniques to develop diagnostic or prognostic markers for non-small cell lung cancer in Egypt. These included the study of Haroun et al.

Bladder Cancer
Chronic inflammation with attendant oxidative stress induced by Schistosomia haematobium infection remains a major cause of bladder cancer in Africa (313)(314)(315), with squamous cell carcinoma being the most common (316,317). Schistosomiasis (or bilharzia) is a neglected tropical disease that is widespread across Africa (318). This cancer is the 10 th most prevalent cancer in Africa and accounted for 240,000 death in 2018. Studies on its genetics/genomics represented about 3% of the publications that we reviewed.
Its pathogenesis involves the bladder infection by S. haemotobium, which induces the formation of carcinogenic N-nitrosamine that contributes to squamous cell carcinogenesis (319), particularly in individuals with TP53 mutation (320). In addition, mutations in genes associated with inflammation and detoxification of carcinogenesis are critical risk factors. One of which is the polymorphisms in CYP2D6 and CYP1A1 that have been studied in Egypt and Tunisia (321)(322)(323) and that of CYP2D*1A, which was found to increase the risk and clinicopathological outcome of both transitional and squamous cell carcinomas in Egypt (322). Similar findings were reported in the same North African countries for individuals with GST null genotypes and NAT*5 (341T>C) (324)(325)(326)(327)(328)(329)(330)(331).
The pattern of CpG island hypermethylation was studied by Gustierrez et al. (344) and they showed that the Schistosomaassociated tumors in Egyptian patients had higher hypermethylation of genes like E-cadherin, DAP-kinase, TP14, TP15, TP16, APC, GSTP1, and TP73. Other authors have further proposed using these unique epigenetic modifications for the early diagnosis of bladder cancer by utilizing plasma circulating microRNA and urinary DNA methylation profile (345,346).
It is important to note that pesticides have also been implicated in bladder tumorigenesis (347, 348) through oxidative stress and KRAS mutation in Egyptian occupationallyexposed individuals (347).
The genomic studies on the cancer of the brain, kidney, pancreas, and other organs are still emerging with very limited publications (366)(367)(368)(369)(370)(371)(372)(373)(374)(375)(376)(377)(378). The emphasis of these publications on the polymorphisms of genes associated with inflammatory response is an indication of the importance of this biological process to the neoplastic transformation of normal tissue and the progression of the malignancy. In addition, studies on retinoblastoma concentrated on identifying the constitutional mutations in RB within the North African populations (379)(380)(381)(382) while publications on esophageal and gastric cancers focused on identifying the role of RAS genes mutations as drivers of genomic instability (383)(384)(385)(386).

Lymph and Hematological Malignancies
The most prevalent lymphoma in Africa is Burkitt lymphoma. Its pattern and geographical spread are similar to that of malaria and ancient human migration on the continent (387)(388)(389)(390)(391)(392). This aggressive pediatric B-cell non-Hodgkin lymphoma is caused by the EBV, which induces genomic instability in the B-cell that results in hyperproliferation (393,394) and it is associated with unique TP53 mutations that are clustered between codons 213 to 248 (395-397).
Other studies on lymphoma include: (1) the role of TP73 and FOXP3 in the pathogenesis of reactive lymphoid hyperplasia and diffuse B-cell lymphoma, as well as the contribution of HLA-G polymorphism to non-Hodgkin lymphoma in Egypt (398-400), (2) susceptibility of individuals with A/A genotype of TNF promoter (-308A/G) to non-Hodgkins lymphoma in Tunisia (401) and Egypt (402) and the identification of HLA-B*18, DRB1*03, DRB1*07, and DQB1*02 as lymphoma susceptibility loci in Algerian children (403).

DISCUSSION
In order to provide an overview of research progress in African cancer genomics with the view of identifying the critical gaps, we searched and reviewed publications on cancer genetics and genomics in Africa. The 375 publications on cancer genetics/ genomics retrieved on PubMed represented only 0.016% of total publications on cancer globally.
According to the 2018 GLOBOCAN data on cancer in Africa, the most frequently diagnosed cancers were breast, cervix, prostate, liver, and colorectum, while the leading causes of cancer deaths were from cancers of the cervix, breast, prostate, liver, and colorectum (2). However, of the top ten frequently diagnosed cancers and the leading cause of cancer deaths in Africa, only breast, colorectal, liver, and ovarian cancers were proportionately represented in cancer genetics/genomics studies returned from search terms.
Overall, Africans are grossly underrepresented in cancer genomics and molecular biology research globally. For example, research on prostate cancer in African men or breast cancer in African women, both leading causes of death in Africa, are still understudied compared to cancers in their non-Black and white counterparts (412).
Although Africa seems to be on the right track in terms of focusing on some of the top cancers, researchers and funding agencies, need to elevate and prioritize genetics and genomics research on cancers that remain hugely underrepresented or unrepresented in the literature for which there is a significant burden in Africa. These include cancers of the lung, ovary, stomach, bladder, prostate, and non-Hodgkin lymphoma, which are among the leading ten causes of death but remain understudied in the literature. Filling this research gap is essential to improving awareness, prevention, diagnosis, and treatment outcomes for people affected by cancer across the continent.
It is also worth noting that most studies on cancer in Africa are clustered to a few regions, mainly North Africa, Nigeria, Ghana, and South Africa. Most of the continent lacks any appreciable data, is often excluded from research efforts, and is devoid of the infrastructure and resources needed to contribute to cancer genomics/genetics discoveries.
It is important to reiterate that this review was based on publications that were indexed in Pubmed only. This is because Pubmed is considered as the most reputable index for biomedical publications, and the data we have retrieved are a good representation of the spectrum and scope of this review. It is also possible that our search did not retrieve some studies that included African populations, and this could be because those studies were not focused on African countries or groups but have used them for comparative purposes, thereby making the data obscure and less prominent in their findings. The use of MeSH terms ensured that relevant publications were extracted from Pubmed.

CONCLUSION AND FUTURE DIRECTIONS
As presented in this review, the preponderance of the peerreviewed publications on cancer genomics in Africa was on the North Africa populations. Hence, there is a need for a concerted effort to address the gaps in the contribution of genomic variance and alterations to cancer in Sub-Saharan African populations.
Recently, Durvasula and Sankararaman (413) reported the presence of ghost archaic introgression into the genome of Sub-Saharan Africa populations, and some of this introgression included regions involved in carcinogenesis. This and the details presented in this review lay credence to the inadequacy of the use of predominantly Caucasian genomics data for cancer control in Africa. The use of personalized medicine and targeted therapy in cancer management rely on understanding the genomics of the population. Hence, there is a need to step up cancer genomics studies for Africa to benefit from medical advances. Also, because Africa is the root of humanity, understanding the genetic basis of this disease in Africans will contribute to improving cancer health equity globally.
In addition, scientific investigations on cancer racial disparity have largely considered the Black race as a homogenous group. However, the evidence is now emerging that there are withingroup differences in cancer risk among Blacks (414). This review also clearly demonstrated the need to disaggregate Africa in cancer studies. To reduce cancer disparity and achieve equity in treatment outcomes, cancer genetics and genomics studies in African should endeavor to stratify populations by their ancestry roots, tribes, or languages rather than countries. This is imperative to identifying population-relevant genetic variants since African countries are geopolitical constructs that bear no relationship with the biological relatedness of the people that are clustered together in those countries.
Furthermore, every genomic study requires a reference to make an appropriate inference, but African populations are presently inadequately represented in the current reference genomes. To address this unmet need, Shermanet et al. (415) recently published a pan-African reference genome. The African Pan Genome sequences they assembled revealed that up to 10% of the genome will be missed by any efforts relying only on GRCh38 to study human variation. Yet, it is important to note that their study only included representative samples (5%) from Ibadan, Nigeria, and may not be a true "Pan African Genome" and may best represent the West African human population, which the Yoruba people belong to. Further research efforts are, therefore, needed to assemble more African reference genomes, which should be based on the genetic divergence of human populations in Africa.

AUTHOR CONTRIBUTIONS
BS conceived, designed, and supervised the review. SR and OR collected and analyzed the data. BS, SR, and OR wrote the manuscript. All authors contributed to the article and approved the submitted version.