Inherited forms of breast and ovarian cancers (those due to germline inheritance of mutations in single genes) account for about 5% of all cases of these cancers. Study of families predisposed to breast and particularly ovarian cancer has been an active area of research for several decades through NCI's Familial Cancer Registry. Since the cloning of the BRCA1 gene in 1994 and the BRCA2 gene in 1995, the two genes thought to account for about 2/3 of inherited breast and ovarian cancers, mutational analysis has revealed a very large number of mutations, most leading to truncated proteins. The technical difficulty of detecting relatively rare mutations in these two large genes has hampered large-scale population-based studies of them. However, in the initial analysis of the NCI breast and ovarian cancer families, a recurrent BRCA1 mutation, called 185delAG, was detected in three Ashkenazi Jewish families. Subsequent studies in collaboration with the National Human Genome Research Institute (NHGRI) revealed that about 1% of the Ashkenazi Jewish population carries this mutation. Another BRCA1 mutation, called 5382insC, is present in about 0.1% of the Ashkenazi population. Also, our studies and others determined that a founder BRCA2 mutation, designated 6174delT, is carried by slightly over 1% of the Ashkenazi population. Overall, the carrier frequency for these three specific mutations is nearly 1 in 40 among Jews. The high carrier frequency and the relative ease of detecting a small number of mutations (compared to complete sequencing of the BRCA1 and BRCA2 genes) has provided an excellent opportunity to conduct population-based studies of these genes in founder populations. Analyses are ongoing with the Washington Ashkenazi Survey dataset, including analyses on carrier frequency and survival after breast cancer. A collaborative study in Iceland, in which a single BRCA2 mutation is present in about 0.5% of the population, led to an estimated 37% risk of breast cancer by age 70 using the kin-cohort method. We are collaborating with investigators in Israel on a large ovarian cancer case-control study in which over 800 cases and 800 controls will be analyzed for the three common founder mutations among Jews. A collaborative genetic counseling and testing study is continuing with NHGRI investigators.
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