Molecular Genetic Testing of Breast and Ovarian Cancer

BRCA1 and BRCA2 are well known breast cancer susceptibility genes responsible for 30-70% of hereditary breast and ovarian cancer. Germline mutations in these genes confer greatly increased risk for breast and ovarian cancer. Mutation prevalence varies widely among different populations, and may be influenced by founder mutations. Our studies of sporadic breast and ovarian cancer in the Hong Kong Chinese population identified somatic mutations and found an 11.3% incidence of BRCA1 germline mutations in ovarian cancer with insignificant family history. Five recurrent mutations were identified, three of which demonstrated founder effect in Chinese. While breast cancers with BRCA1 mutation are mainly of basal-like phenotype, the phenotype of BRCA2 tumors is more heterogenous. BRCA1 and BRCA2 mutations are sufficiently common in ovarian cancers of high-grade serous type to suggest genetic testing of all such patients. Epigenetic silencing of BRCA1 is found in both breast and ovarian cancers. In ovarian cancers, BRCA1 epigenetic silencing has been shown associated with high-grade serous type. BRCA1 dysfunction caused by changes in transcription regulation can also play a role in sporadic basal-like breast cancers. Our analysis of 30 sporadic ovarian cancers showed BRCA1 hypermethylation but BRCA2 hypomethylation, with opposing mRNA expression and methylation patterns found in the BRCA1 and BRCA2 genes within the same cases. Promoter polymorphisms can alter the binding affinity of transcription factors, changing transcriptional activity and thus gene expression. We have identified 4 promoter polymorphisms in the Hong Kong Chinese population, which can significantly alter promoter activity, the most significant contribution being from -969C/T. Genetic association analysis of two independent case-control cohorts of Chinese women totaling >3000 participants demonstrated significantly reduced risk to breast cancer for -969T carriers. Together with gene-expression regulation by epigenetic mechanisms, germ-line promoter polymorphism may also make an important contribution towards breast and/or ovarian cancer development