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Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers

¹ Abramson Cancer Center, ² Center for Clinical Epidemiology and Biostatistics, and ³ Department of Medicine, The University of Pennsylvania School of Medicine; ⁴ Population Science Division, Fox Chase Cancer Center, Philadelphia, Pennsylvania; ⁵ Queensland Institute of Medical Research, Brisbane, Queensland, Australia; ⁶ Peter MacCallum Cancer Center, Melbourne, Victoria, Australia; ⁷ Department of Obstetrics and Gynaecology, Medical University Vienna, Vienna, Austria; ⁸ Division of Epidemiology, Department of Medicine, University of California, Irvine, California; ⁹ Departments of Medicine and Preventive Medicine and Public Health, Creighton University, Omaha, Nebraska; ¹⁰ Department of Medicine, Harvard Medical School and Dana-Farber Cancer Institute; ¹¹ Beth Israel Deaconess Medical Center, Boston, Massachusetts; ¹² City of Hope Comprehensive Cancer Center, Duarte, California; ¹³ Lombardi Cancer Center, Georgetown University, Washington, District of Columbia; ¹⁴ Mayo Clinic College of Medicine, Rochester, Minnesota; ¹⁵ Women's College Hospital, Toronto, Ontario, Canada; ¹⁶ NorthShore University HealthSystem, Evanston, Illinois; ¹⁷ Department of Internal Medicine and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center; ¹⁸ Baylor-Charles A. Sammons Cancer Center, Dallas, Texas; ¹⁹ Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas; ²⁰ Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, California; and ²¹ University of Chicago, Chicago, Illinois

Requests for reprints: Timothy R. Rebbeck, Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, 217 Blockley Hall, Philadelphia, PA 19104-6021. Phone: 215-898-1793; Fax: 215-573-1050; E-mail: rebbeck{at}mail.med.upenn.edu.

Key Words: genetic susceptibility • ovarian cancer • risk modifiers

Inherited BRCA1/2 mutations confer elevated ovarian cancer risk. Knowledge of factors that can improve ovarian cancer risk assessment in BRCA1/2 mutation carriers is important because no effective early detection for ovarian cancers exists. A cohort of 1,575 BRCA1 and 856 BRCA2 mutation carriers was used to evaluate haplotypes at ATM, BARD1, BRIP1, CTIP, MRE11, NBS1, RAD50, RAD51, and TOPBP1 in ovarian cancer risk. In BRCA1 carriers, no associations were observed with ATM, BARD1, CTIP, RAD50, RAD51, or TOPBP1. At BRIP1, an association was observed for one haplotype with a multiple testing corrected P (P_corr) = 0.012, although no individual haplotype was significant. At MRE11, statistically significant associations were observed for one haplotype (P_corr = 0.007). At NBS1, we observed a P_corr = 0.024 for haplotypes. In BRCA2 carriers, no associations were observed with CTIP, NBS1, RAD50, or TOPBP1. Rare haplotypes at ATM (P_corr = 0.044) and BARD1 (P_corr = 0.012) were associated with ovarian cancer risk. At BRIP1, two common haplotypes were significantly associated with ovarian cancer risk (P_corr = 0.011). At MRE11, we observed a significant haplotype association (P_corr = 0.012), and at RAD51, one common haplotype was significantly associated with ovarian cancer risk (P_corr = 0.026). Variants in genes that interact biologically withBRCA1 and/or BRCA2 may be associated with modified ovarian cancer risk in women who carry BRCA1/2 mutations. [Cancer Res 2009;69(14):5801–10]