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 NCIs 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.
| Chodick, Gabriel; Struewing, Jeffery P; Ron, Elaine et al. (2008) Similar prevalence of founder BRCA1 and BRCA2 mutations among Ashkenazi and non-Ashkenazi men with breast cancer: evidence from 261 cases in Israel, 1976-1999. Eur J Med Genet 51:141-7 |
| Struewing, J P; Pineda, M A; Sherman, M E et al. (2006) Skewed X chromosome inactivation and early-onset breast cancer. J Med Genet 43:48-53 |
| Garcia-Closas, Montserrat; Egan, Kathleen M; Newcomb, Polly A et al. (2006) Polymorphisms in DNA double-strand break repair genes and risk of breast cancer: two population-based studies in USA and Poland, and meta-analyses. Hum Genet 119:376-88 |
| Stredrick, Denise L; Garcia-Closas, Montserrat; Pineda, Marbin A et al. (2006) The ATM missense mutation p.Ser49Cys (c.146C>G) and the risk of breast cancer. Hum Mutat 27:538-44 |
| Ellis, Nathan A; Kirchhoff, Tomas; Mitra, Nandita et al. (2006) Localization of breast cancer susceptibility loci by genome-wide SNP linkage disequilibrium mapping. Genet Epidemiol 30:48-61 |
| Spurdle, Amanda B; Antoniou, Antonis C; Kelemen, Livia et al. (2006) The AIB1 polyglutamine repeat does not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev 15:76-9 |
| McInerney-Leo, Aideen; Biesecker, Barbara Bowles; Hadley, Donald W et al. (2005) BRCA1/2 testing in hereditary breast and ovarian cancer families II: impact on relationships. Am J Med Genet A 133:165-9 |
| Mateus Pereira, Lutecia H; Sigurdson, Alice J; Doody, Michele M et al. (2004) CHEK2:1100delC and female breast cancer in the United States. Int J Cancer 112:541-3 |
| Wacholder, Sholom; Struewing, Jeffery P; Hartge, Patricia et al. (2004) Breast cancer risks for BRCA1/2 carriers. Science 306:2187-91; author reply 2187-91 |
| Struewing, Jeffery P; Hartge, Patricia; Wacholder, Sholom et al. (2004) BRCA1 and sex ratio. Eur J Hum Genet 12:663-7 |
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