Ovarian cancer is the most lethal gynaecological
malignancy and it most commonly occurs in postmenopausal women. Ninety per cent of
ovarian cancers are derived from the ovarian surface epithelium and these
neoplasms are classified into serous, mucinous, endometrioid, clear-cell and transitional-cell types. The molecular pathology of ovarian
carcinomas is heterogeneous and involves various putative precursor lesions and multiple pathways of development. The most common subtype, high-grade serous
carcinoma, is characterized by p53 mutations, and BRCA1 and/or BRCA2 dysfunction. It most likely arises from epithelium within inclusion
cysts or from the surface of the ovary. In contrast, low-grade serous
carcinomas are characterized by KRAS or BRAF mutations and appear to arise via an
adenoma-borderline-
carcinoma sequence. Similarly,
mucinous carcinomas have KRAS mutations and probably develop via an
adenoma-borderline-
carcinoma sequence. Low-grade
endometrioid carcinomas, however, are characterized by mutations in PTEN and CTNNB1, and
microsatellite instability, and may arise from ovarian
endometriosis or borderline endometrioid tumours. High-grade
endometrioid carcinomas have similar changes to high-grade serous
carcinomas. Clear-cell
carcinomas are characterized by mutations of TGFbetaR2 and over-expression of
HNF-1beta, and probably arise from ovarian
endometriosis. The molecular changes in
transitional-cell carcinomas of the ovary remain largely unknown. The identified molecular changes and pathways of development in
epithelial ovarian cancer will facilitate the rationalized development of new diagnostic modalities and tailored
therapies for this
malignancy.