BRCA1- and BRCA2-Associated Ovarian Cancer: different diseases?

Abstract

Ovarian cancer will develop in approximately 1.4% of the Dutch women accounting for approximately 1250 new patients yearly in the Netherlands, which is comparable with the incidence in other Western world countries. The disease mainly develops in women of 40 years of age and older, with the highest incidence around 60 years of age. Despite this relatively low incidence, ovarian cancer is the leading cause of death from gynaecological malignancies in the Netherlands, with about 1000 deaths annually. Ninety per cent of all ovarian cancers are of epithelial origin, and therefore can exhibit features of the different epithelia originating from the Mullerian ducts i.e. the epithelium lining the fallopian tubes, cervix, uterus, and part of the vagina. In this way, epithelial ovarian cancers (EOC) can be subdivided into serous, mucinous, endometrioid, clear cell, undifferentiated carcinomas and Brenner tumors.Most ovarian cancers are of serous histology (65-70%). Traditionally, differentiation grade has been classified in grade 1, 2 and 3, according to the Silverberg criteria. More recently another classification system for ovarian cancer has been introduced, subdividing into low-grade (Type I) and high-grade (Type II) tumors. Low-grade tumors have frequent mutations in the KRAS, BRAF, ERBB2, CTNNB1, PTEN, PIK3CA, ARID1A, and PPP2R1A genes, lack TP53 mutations and have a better outcome than high-grade tumors.Low-grade carcinomas exhibit low-grade nuclei with infrequent mitotic figures. This entity comprises low-grade serous, low-grade endometrioid, clear cell and mucinous carcinomas and Brenner tumors. High-grade carcinomas have high-grade nuclei and numerous mitotic figures, feature a high growth rate, are characterized by TP53 mutations and lack mutations of KRAS, BRAF, or ERBB2 and have molecular alterations that disturb expression of BRCA either by a mutation in the gene or by promoter methylation. High-grade carcinomas are assumed to originate de novo and comprise high-grade serous, high-grade endometrioid, mixed mesodermal tumors (carcinosarcomas) and undifferentiated carcinomas.