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Characterization of BRCA1 and BRCA2 Mutations in a Large United States Sample

From the Departments of Environmental Health Sciences and Biostatistics, Johns Hopkins Bloomberg School of Public Health; The Sidney Kimmel Comprehensive Cancer Center and the Department of Biostatistics, Johns Hopkins University, Baltimore, MD; Departments of Biostatistics and Bioinformatics and Community and Family Medicine, Duke University, Durham, NC; Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA; The Massachusetts General Hospital, Boston, MA; Translational Medicine and Genetics, GlaxoSmithKline, West Chester, PA; Preventive Oncology and Medical Oncologist, Toronto Sunnybrook Regional Cancer Centre, Toronto, Ontario, Canada; Departments of Medicine and Molecular and Human Genetics, Baylor College of Medicine; Departments of Epidemiology, Molecular Genetics, and Biostatistics, University of Texas M.D. Anderson Cancer Center, Houston; Departments of Pediatrics and Surgery, University of Texas Southwestern, Dallas, TX; Georgetown University Lombardi Cancer Center, Washington, DC; and Huntsman Cancer Center, University of Utah, Salt Lake City, UT

Address reprint requests to Sining Chen, MD, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, W7041, Baltimore, MD 21205; e-mail: sichen{at}jhsph.edu

PURPOSE: An accurate evaluation of the penetrance of BRCA1 and BRCA2 mutations is essential to the identification and clinical management of families at high risk of breast and ovarian cancer. Existing studies have focused on Ashkenazi Jews (AJ) or on families from outside the United States. In this article, we consider the US population using the largest US-based cohort to date of both AJ and non-AJ families.

METHODS: We collected 676 AJ families and 1,272 families of other ethnicities through the Cancer Genetics Network. Two hundred eighty-two AJ families were population based, whereas the remainder was collected through counseling clinics. We used a retrospective likelihood approach to correct for bias induced by oversampling of participants with a positive family history. Our approach takes full advantage of detailed family history information and the Mendelian transmission of mutated alleles in the family.

RESULTS: In the US population, the estimated cumulative breast cancer risk at age 70 years was 0.46 (95% CI, 0.39 to 0.54) in BRCA1 carriers and 0.43 (95% CI, 0.36 to 0.51) in BRCA2 carriers, whereas ovarian cancer risk was 0.39 (95% CI, 0.30 to 0.50) in BRCA1 carriers and 0.22 (95% CI, 0.14 to 0.32) in BRCA2 carriers. We also reported the prospective risks of developing cancer for cancer-free carriers in 10-year age intervals. We noted a rapid decrease in the relative risk of breast cancer with age and derived its implication for genetic counseling.

CONCLUSION: The penetrance of BRCA mutations in the United States is largely consistent with previous studies on Western populations given the large CIs on existing estimates. However, the absolute cumulative risks are on the lower end of the spectrum.

Supported in part by the National Cancer Institute Cancer Genetics Network. Also supported in part by National Cancer Institute grant Nos. P50CA88843, P50CA62924-05, 5P30 CA06973-39, and R01CA105090 and National Institutes of Health grant No. HL 99-024 and the Hecht Fund (G.P., S.C., T.F.). Work of investigators from Georgetown University was partly supported by Cancer Genetics Network grant No. CA78146-01 and by the Familial Cancer Registry Shared Resource of the Lombardi Comprehensive Cancer Center, which receives partial support from National Institutes of Health grant No. P30-CA-51008. D.F. is supported by Cancer Genetics Network grant No. CA78284.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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