Prevalence of BRCA Mutations and Founder Effect in High-Risk Hispanic Families Jeffrey N. Weitzel, 1 Veronica Lagos, 1 Kathleen R. Blazer, 1 Rebecca Nelson, 2 Charite ´ Ricker, 1 Josef Herzog, 1 Colleen McGuire, 3 and Susan Neuhausen 4 Departments of 1 Clinical Cancer Genetics and 2 Information Sciences, City of Hope Cancer Center, Duarte, California; 3 Cancer Risk Program, St. Joseph Hospital Regional Cancer Center, Orange, California; and 4 Division of Epidemiology, Department of Medicine, University of California Irvine, Irvine, California Abstract Approximately 12% of the U.S. population is Hispanic, with the majority residing in urban centers such as Los Angeles. The prevalence of BRCA mutations among high-risk His- panic families is unknown. Methods: One hundred and ten unrelated probands of His- panic origin, with a personal or family history of breast and/ or ovarian cancer, presented for genetic cancer risk assessment, were enrolled in an Institutional Review Board–approved registry and underwent BRCA testing. Haplotype analyses were done if BRCA mutations were observed in two or more unrelated probands. Results: Mean age at diagnosis was 37 years (range = 23-59) for the 89 (81%) probands with invasive breast cancer. Overall, 34 (30.9%) had deleterious mutations (25 in BRCA1 , 9 in BRCA2 ), 25 (22.7%) had one or more unclassified variants, and 51 (46.4%) had negative results. The mean pretest mutation probability using the Couch model, Myriad model, and BRCAPro was 19.6% (range = 4- 77%). The combined average mutation probability was 32.8% for carriers, 15.5% for noncarriers, and 12.9% for variant carriers (P < 0.0001). The most common deleterious mutation was 185delAG (4 of 34, 11.8%). The Hispanic 185delAG carrier families share the same haplotype from D17s1320 through BRCA1 , as do two reference Ashkenazi Jewish families. Haplotype analyses of additional recurrent BRCA1 mutations [IVS5+1G>A (n = 2), S955X (n = 3), R1443X (n = 3), and 2552delC (n = 2)] also suggest founder effects, with four of six mutations seen almost exclusively in families with Latin American/Caribbean or Spanish ancestry. Conclusion: This is the largest study to date of high-risk Hispanic families in the United States. Six recurrent mutations accounted for 47% (16 of 34) of the deleterious mutations in this cohort. The BRCA1 185delAG mutation was prevalent (3.6%) in this clinic-based cohort of predom- inantly Mexican descent, and shared the Ashkenazi Jewish founder haplotype. (Cancer Epidemiol Biomarkers Prev 2005;14(7):1666–71) Introduction Breast cancer is the most commonly diagnosed cancer in Hispanic women, and is the leading cancer cause of death, exceeding even lung cancer. Approximately 12% of the U.S. population is Hispanic, 5 with rates expected to increase to 25% by 2050 (U.S. Census Data 2000). Whereas only 5% to 10% of breast and ovarian cancers are associated with mutations in BRCA1 or BRCA2 , there are thousands of pre- valent cancer cases attributable to genetic predisposition. The magnitude of risk in hereditary cancer families is large. The lifetime risk of developing breast cancer associated with a BRCA mutation may be as high as 85% and the lifetime risk of ovarian cancer may be up to 44% (1). Genetic susceptibility to breast cancer has been observed in most races and ethnicities (2-8). Genetic cancer risk assessment is an emerging interdisci- plinary subspecialty and genetic testing for inherited breast cancer susceptibility has become a state-of-the-art standard of care option for appropriately selected patients (9-11). Features such as early-onset breast cancer (under the age of 40 years), bilateral disease, or family history of breast and/or ovarian cancer are suggestive of genetic predisposition (9). The Hispanic population is not evenly distributed across the United States and consists of a range of individuals from different countries of origin (12). Whereas current trends in the movement of the Hispanic population include extension into more rural areas of the South and Midwest, the vast majority of the population is concentrated in traditional urban centers— almost 7 of every 10 Hispanics live in California, Texas, New York, New Jersey, or Florida (U.S. Census Bureau, 2000 Redistricting Data). The prevalence of BRCA mutations among high-risk Hispanic families in major metropolitan areas is unknown. The purpose of this study was to determine the prevalence of BRCA mutations among Hispanic families attending a high- risk clinic in Southern California. Materials and Methods Subjects. The City of Hope’s Cancer Screening & Prevention Program Network includes cancer center and community- based high-risk clinics that provide genetic cancer risk assessment to individuals with a personal or family history of cancer. All patients presenting for genetic cancer risk assessment were invited to participate in an Institutional Review Board – approved prospective Hereditary Cancer Registry at the time of their initial cancer risk assessment consultation. Ninety-eight percent of candidates chose to 5 Although we use ‘‘Hispanic,’’ the most common census term for individuals of Spanish, Mexican, Central and South American, Cuban, or Puerto Rican descent, referring to ‘‘race,’’ is ‘‘Latino.’’ Latino is generally considered a more ethnically/culturally based term for individuals of the aforementioned groups. Cancer Epidemiology, Biomarkers & Prevention 1666 Cancer Epidemiol Biomarkers Prev 2005;14(7). July 2005 Received 1/26/05; revised 3/30/05; accepted 4/8/05. Grant support: California Cancer Research Program of the University of California grants 99-86874 and 00-92133 and General Clinical Research Center grant M01 RR00043 from NIH awarded to the City of Hope National Medical Center, Duarte, California. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: C. Ricker is currently in the University of Southern California, Los Angeles, CA. Requests for reprints: Jeffrey N. Weitzel, Department of Clinical Cancer Genetics, City of Hope Cancer Center, 1500 East Duarte Road, Mod 103, Duarte, CA 91010. Phone: 626-256-8662; Fax: 626-930-5495. E-mail: jweitzel@coh.org Copyright D 2005 American Association for Cancer Research. Downloaded from http://aacrjournals.org/cebp/article-pdf/14/7/1666/1748873/1666-1671.pdf by guest on 30 June 2022