Epithelial ovarian cancer (EOC) is the most lethal gynecological disorder due to a lack of effective early detection strategies. Worldwide, approximately 230,000 women are diagnosed annually, whereas 150,000 die. It represents the seventh most commonly diagnosed cancer among women in the world with 5-year survival rate of 46%. More than one-fifth of EOC have been related to hereditary conditions.
Considerable efforts have been made to implement screening of the general population to diagnose EOC early; nevertheless, this has been ineffective and there is no approved strategy. Nowadays, new approaches for early diagnosis and prevention based on molecular genomics are in development. Whole genome sequencing has established the potency of the somatic genome, characterised with diverse DNA repair deficiencies that can be used to stratify EOCs into distinct biological groups with predictive signatures of resistance or relapse. The incorporation of next-generation sequencing (NGS) into clinical practice remains challenging for two reasons. Firstly, the EOC risk is not clear for some of the included genes and secondly, the variant of uncertain significance rates increase as more genes are analyzed. Finally, beyond germline pathogenic variants, somatic mutations may also affect therapeutic choices, and as such upfront tumor sequencing may be equally important to NGS, particularly as we continue to challenge treatment paradigms in the first-line management of EOC.
Homologous recombination (HR) is a mechanism of DNA repair important in the carcinogenesis of this subtype. Particularly, in about 65–85% of hereditary EOC, the genetic abnormality is a germline mutation in breast cancer genes (BRCA) that causes DNA repair defects. Apart from BRCA1/2, several other suppressor genes and oncogenes have been associated with hereditary EOC (i.e., TP53, BARD1, CHEK2, RAD51, and PALB2).
Poly (ADP-ribose) polymerase (PARP) inhibitors exploit HR deficiency, especially in BRCA1/2 mutants. Several agents have been studied in combination with PARP inhibitors. The first PARP inhibitor combinations to be studied were with antiangiogenic agents. It has been demonstrated that PARP inhibition decrease angiogenesis whereas, hypoxic state and vascular endothelial growth factor receptor 3 (VEGFR3) inhibitors induce down-regulation of HR repair proteins, which potentiate PARP inhibitors sensitivity. In addition, encouraging preliminary results support the therapeutic combination of PARP and immune checkpoint inhibitors (ICI). The input of immunotherapy in EOC is based on the observation that immunosuppressive microenvironments can affect tumour growth, metastasis and even treatment resistance. Results from ongoing trials demonstrated better outcomes of the combined strategy as compared to ICI monotherapy. Additional biologic agents that have been combined with PARP inhibitors are the anti-CTLA4 monoclonal antibodies, and the mTOR-, AKT-, PI3K-, MEK1/2-, and WEE1 inhibitors. Finally, combination of PARP inhibitors with chemotherapy has been recommended with the rationale of disrupting base excision repair via PARP inhibition.
Along with VEGF, Notch pathway is essential in EOC angiogenesis, whilst it is also related to chemoresistance. Notch targeting with small-molecule inhibitors or antibodies is a promising treatment in the early stage of development. Furthermore, treatment with metformin in vitro and in vivo has resulted in decreased angiogenesis in metastatic tissues. Furthermore, metformin targets ALDH+ EOC stem cell populations in vitro, resulting in suppressed angiogenesis, invasion and migration capabilities of EOC cells.
Recently, long noncoding RNAs (lncRNAs) have been identified as key regulators of cancer development. Studies have shown that the dysregulation of lncRNAs is frequently observed in EOC and greatly contributes to malignant phenotypical changes.
Patients with endometriosis have an increased risk of EOC, specifically ovarian clear cell carcinoma (OCCC) and endometrioid ovarian carcinoma (EnOC). Genetic studies provide possible mechanistic link between endometriosis and EOC. ARID1A mutations coincide with loss of ARID1A protein expression in OCCC and EnOC. Moreover, conditional homozygous knockout of PTEN may drive EnOC.
Overall, understanding of the basic molecular biology of EOC is extremely important. Comprehensive functional and clinical studies are necessary for validation of potential biomarkers in light of their application as therapeutic treatment. The articles of the Research Topic will help to highlight recent advances in the fields of prevention, molecular biology, genetics, and treatment and should be contributed as Original Research Articles or Reviews. Preclinical and clinical research is equally appreciated.
The manuscripts should be focused but are not only limited to:
-Genetic testing in ovarian cancer
-PARP inhibitors in ovarian cancer
-PARP inhibitors in combination with other therapies
-Immunotherapy in ovarian cancer
-Notch pathway in ovarian cancer angiogenesis
-Metformin and ovarian cancer
-LncRNAs in ovarian cancer
-Endometriosis-associated ovarian carcinomas
-Clinical effectiveness and cost-effectiveness of novel therapies for ovarian cancer
Epithelial ovarian cancer (EOC) is the most lethal gynecological disorder due to a lack of effective early detection strategies. Worldwide, approximately 230,000 women are diagnosed annually, whereas 150,000 die. It represents the seventh most commonly diagnosed cancer among women in the world with 5-year survival rate of 46%. More than one-fifth of EOC have been related to hereditary conditions.
Considerable efforts have been made to implement screening of the general population to diagnose EOC early; nevertheless, this has been ineffective and there is no approved strategy. Nowadays, new approaches for early diagnosis and prevention based on molecular genomics are in development. Whole genome sequencing has established the potency of the somatic genome, characterised with diverse DNA repair deficiencies that can be used to stratify EOCs into distinct biological groups with predictive signatures of resistance or relapse. The incorporation of next-generation sequencing (NGS) into clinical practice remains challenging for two reasons. Firstly, the EOC risk is not clear for some of the included genes and secondly, the variant of uncertain significance rates increase as more genes are analyzed. Finally, beyond germline pathogenic variants, somatic mutations may also affect therapeutic choices, and as such upfront tumor sequencing may be equally important to NGS, particularly as we continue to challenge treatment paradigms in the first-line management of EOC.
Homologous recombination (HR) is a mechanism of DNA repair important in the carcinogenesis of this subtype. Particularly, in about 65–85% of hereditary EOC, the genetic abnormality is a germline mutation in breast cancer genes (BRCA) that causes DNA repair defects. Apart from BRCA1/2, several other suppressor genes and oncogenes have been associated with hereditary EOC (i.e., TP53, BARD1, CHEK2, RAD51, and PALB2).
Poly (ADP-ribose) polymerase (PARP) inhibitors exploit HR deficiency, especially in BRCA1/2 mutants. Several agents have been studied in combination with PARP inhibitors. The first PARP inhibitor combinations to be studied were with antiangiogenic agents. It has been demonstrated that PARP inhibition decrease angiogenesis whereas, hypoxic state and vascular endothelial growth factor receptor 3 (VEGFR3) inhibitors induce down-regulation of HR repair proteins, which potentiate PARP inhibitors sensitivity. In addition, encouraging preliminary results support the therapeutic combination of PARP and immune checkpoint inhibitors (ICI). The input of immunotherapy in EOC is based on the observation that immunosuppressive microenvironments can affect tumour growth, metastasis and even treatment resistance. Results from ongoing trials demonstrated better outcomes of the combined strategy as compared to ICI monotherapy. Additional biologic agents that have been combined with PARP inhibitors are the anti-CTLA4 monoclonal antibodies, and the mTOR-, AKT-, PI3K-, MEK1/2-, and WEE1 inhibitors. Finally, combination of PARP inhibitors with chemotherapy has been recommended with the rationale of disrupting base excision repair via PARP inhibition.
Along with VEGF, Notch pathway is essential in EOC angiogenesis, whilst it is also related to chemoresistance. Notch targeting with small-molecule inhibitors or antibodies is a promising treatment in the early stage of development. Furthermore, treatment with metformin in vitro and in vivo has resulted in decreased angiogenesis in metastatic tissues. Furthermore, metformin targets ALDH+ EOC stem cell populations in vitro, resulting in suppressed angiogenesis, invasion and migration capabilities of EOC cells.
Recently, long noncoding RNAs (lncRNAs) have been identified as key regulators of cancer development. Studies have shown that the dysregulation of lncRNAs is frequently observed in EOC and greatly contributes to malignant phenotypical changes.
Patients with endometriosis have an increased risk of EOC, specifically ovarian clear cell carcinoma (OCCC) and endometrioid ovarian carcinoma (EnOC). Genetic studies provide possible mechanistic link between endometriosis and EOC. ARID1A mutations coincide with loss of ARID1A protein expression in OCCC and EnOC. Moreover, conditional homozygous knockout of PTEN may drive EnOC.
Overall, understanding of the basic molecular biology of EOC is extremely important. Comprehensive functional and clinical studies are necessary for validation of potential biomarkers in light of their application as therapeutic treatment. The articles of the Research Topic will help to highlight recent advances in the fields of prevention, molecular biology, genetics, and treatment and should be contributed as Original Research Articles or Reviews. Preclinical and clinical research is equally appreciated.
The manuscripts should be focused but are not only limited to:
-Genetic testing in ovarian cancer
-PARP inhibitors in ovarian cancer
-PARP inhibitors in combination with other therapies
-Immunotherapy in ovarian cancer
-Notch pathway in ovarian cancer angiogenesis
-Metformin and ovarian cancer
-LncRNAs in ovarian cancer
-Endometriosis-associated ovarian carcinomas
-Clinical effectiveness and cost-effectiveness of novel therapies for ovarian cancer
