Genetics of Susceptibility to Sporadic Ovarian Cancer

Abstract Specific abnormalities involvingTP53, BRCA 1, BRCA 2, KRAS, BRAF, ERBB2, PIK3CA, PTEN, CTNNB1andARID1Agenes 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.TP53andBRCA 1andBRCA 2gene mutations are associated with high‐grade serous and high‐grade endometrioid subtypes andKRAS, BRAF, ERBB2, PIK3CA, PTEN, CTNNB1andARID1Aalterations are responsible for the development of low‐grade serous, low‐grade endometrioid, clear cell and mucinous subtypes of OEC. Tumours withTP53mutations uniformly carry a worse prognosis and the presence ofBRCA 1and2mutations 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 includingKRAS, BRAF, ERBB2, PTEN, PIK3CA, CTNNB1andARID1A. Type 2 tumours are genetically highly unstable and harbourTP53, BRCA 1andBRCA 2mutations. 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 ofTP53mutations correlates with high grade tumours and poor prognosis. The presence of mutations ofBRCA 1andBRCA 2genes indicate good treatment response to platinum compounds and PARP inhibitors.