Hereditary Ovarian Cancer mutation frequencies and genetic profiles

Abstract: Ovarian cancer is a leading cause of gynecological cancer death and in Sweden nearly 700 cases are diagnosed annually. Ovarian cancer has one of the highest frequencies of hereditary cancer. This thesis focuses on estimates of the contribution of hereditary breast and ovarian cancer (HBOC) and hereditary nonpolyposis colorectal cancer (HNPCC) to the development of ovarian cancer and investigates the genomic profiles in HBOC associated ovarian cancer. In a prospective population-based study, mutations in BRCA1 and BRCA2 were assessed in 161 patients (study I) and mismatch repair (MMR) status was assessed using MMR protein immunostaining from 128 of these tumors (study II). BRCA mutations suggestive of HBOC were identified in 10% of the patients and an additional 2% had MMR defective tumors suggestive of HNPCC. Whereas more than half of the women with HBOC were diagnosed after age 50, the women with HNPCC were young. We therefore investigated the contribution of defective MMR in a population-based cohort of 99 young under age 40 women with ovarian cancer (study III). MMR defects were found in 6% of the tumors, which together with previous studies suggest that HNPCC and HBOC contribute equally to ovarian cancer development in young women. HBOC associated ovarian cancer does not differ clinically and histopathologically from sporadic cancer and we therefore aimed to study whether a hereditary genomic profile could be identified. Genetic complexity was demonstrated in the vast majority of the 12 BRCA1 associated and 25 sporadic ovarian cancers. Gains and high-level amplifications were particularly common in the sporadic tumors, whereas losses characterized the hereditary tumors with losses of 4q, 8p, 13q, 18p, and 19p being significantly more common in the HBOC associated ovarian cancers.