Genetics of Susceptibility to Sporadic Ovarian Cancer

Specific abnormalities involving TP53, BRCA 1, BRCA 2, KRAS, BRAF, ERBB2, PIK3CA, PTEN, CTNNB1 and ARID1A genes are responsible for the development of sporadic ovarian epithelial carcinoma (OEC). Recent advances in the field of cytogenetics and molecular biology have led to the development of an innovative classification of OEC that integrates the anatomical, clinical findings with molecular abnormalities and helps in prognostification and assessment of treatment response. TP53 and BRCA 1 and BRCA 2 gene mutations are associated with high-grade serous and high-grade endometrioid subtypes and KRAS, BRAF, ERBB2, PIK3CA, PTEN, CTNNB1 and ARID1A alterations are responsible for the development of low-grade serous, low-grade endometrioid, clear cell and mucinous subtypes of OEC. Tumours with TP53 mutations uniformly carry a worse prognosis and the presence of BRCA 1 and 2 mutations predicts the positive treatment response to platinum compounds and Poly adenosine diphospahate (ADP) ribose polymerase (PARP) inhibitors. Evolving knowledge regarding the role of different genetic abnormalities in the oncogenesis of sporadic OEC may lead to the identification of ‘small molecules’ that can be used in the discovery of new drugs as well as biomarkers for screening, prognosis, and therapeutic response in the near future. Key Concepts: Ovarian epithelial carcinoma is categorised into two subgroups designated type 1 and type 2, which differ significantly in the pathogenesis, clinic-biologic behaviour, and prognoses. Type 1 tumours are genetically stable and display mutations involving different genes including KRAS, BRAF, ERBB2, PTEN, PIK3CA, CTNNB1 and ARID1A. Type 2 tumours are genetically highly unstable and harbour TP53, BRCA 1 and BRCA 2 mutations. High-grade serous carcinoma and low-grade serous carcinomas develop from fallopian tube epithelium and serve as the prototypes of type 2 and type 1 pathway respectively. Low-grade endometrioid carcinomas and clear cell carcinomas commonly develop from endometriotic cysts. The presence of TP53 mutations correlates with high grade tumours and poor prognosis. The presence of mutations of BRCA 1 and BRCA 2 genes indicate good treatment response to platinum compounds and PARP inhibitors. Keywords: TP53; BRCA 1; BRCA 2; KRAS; BRAF; PTEN; ovarian epithelial carcinomas

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