Genetics of Ovarian Carcinomas

It is estimated that 15–20 % of ovarian carcinomas arise in women carrying a monoallelic germline cancer-predisposing gene mutation. The two main known hereditary forms of ovarian carcinoma are hereditary breast/ovarian cancer (HBOC) linked to BRCA1 or BRCA2 mutations, genes involved in DNA double-strand break repair by homologous recombination (HR), and Lynch syndrome linked to mutations in genes involved in DNA mismatch repair (MMR): MLH1, MSH2, MSH6 or PMS2. The contribution of BRCA1/BRCA2 mutations is at least tenfold higher than that of MMR genes. Identification of a cancer-predisposing mutation is useful for the prevention of breast, ovarian or colon cancers in affected women and their relatives and is now becoming a major part of the treatment of women with ovarian carcinoma, as poly-ADP-ribose-polymerase (PARP) inhibitors have been demonstrated to be useful in HBOC syndrome. New perspectives are opening up in Lynch syndrome with immunotherapy targeting Lynch syndrome-related cancers, characterised by their immunogenicity. Other genes involved in the HR pathway (PALB2, RAD51, ATM) are good candidates to be associated with an increased risk of ovarian and breast cancers that would be expected to be also sensitive to PARP inhibitors. As the identification of women harbouring germline or tumour inactivation of HR genes and probably, in the near future, MMR gene mutations is now becoming essential for their treatment, increasing test demands and the need for rapid and complete analyses are going to modify current genetic counselling and testing practices.