Much of my work involves the detailed mutational epidemiology of BRCA1/2-related cancers. Among families with many cases of breast and ovarian cancer occurring in patterns reminiscent of autosomal dominant Mendelian inheritance, approximately 2/3 have mutations in BRCA1 or BRCA2, two genes identified by positional cloning techniques in 1994 & 1995. Germline mutations occur throughout these large genes and analysis typically requires comprehensive screening of more than 10 kilobases of mRNA encoding sequences. Within the initial set of NCI breast-ovarian cancer families I analyzed, three Ashkenazi Jewish families carried the BRCA1-185delAG frameshift mutation. This led to our observation that approximately 1% of unselected Ashkenazi Jews carry this mutation. Subsequent studies have confirmed this observation and also determined that another BRCA1 mutation, 5382insC, and a very common mutation in BRCA2, 6174delT, together occur in approximately 1 in 40 Ashkenazi Jews, accounting for approximately 80% of all BRCA1/2 mutations in this population. These observations were an entr into more population-based genetic epidemiology studies that I have lead. It is possible to rapidly test for the three founder mutations in large numbers of Ashkenazi subjects, and our estimates of the penetrance, or risk of cancer among subjects who carry germline mutations in BRCA1 or BRCA2, were well below prior estimates from multiple-case families. Subsequent studies in both isolated and outbred populations have generally confirmed that the average penetrance for breast cancer is roughly 50-60% by age 70. Ongoing areas of research include more efficient BRCA1/2 mutation detection methods, delineation of the full cancer risk spectrum among mutation carriers, and the identification of genetic and environmental modifiers. We are comparing the mRNA expression patterns in lymphoblasts from BRCA1 mutation carriers versus relatives without a mutation using Affymetrix microarrays. I am collaborating with an internations group of investigators testing candidate susceptibility alleles in a combined group of mutation carriers from several outbred populations. These studies are challenging for a number of reasons, including the difficulty faced in identifying a large and representative group of mutation carriers, particularly elderly female mutation carriers without breast or ovarian cancer. To this end, as co-investigator, I am coordinating mutation testing for a large, prospective study of oophorectomy in women at high genetic risk of ovarian cancer, which targets enrolling approximately 800 BRCA1/2 mutation carriers.
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