Award Number: W81XWH-04-1-0588 TITLE: Aurora-A as a Modifier of Breast Cancer Risk in BRCA1/2 Mutation Carriers

The AURKA oncogene is associated with abnormal chromosome segregation and aneuploidy and predisposition to cancer. Amplification of AURKA has been detected at higher frequency in tumors from BRCA1 and BRCA2 mutation carriers than in sporadic breast tumors, suggesting that overexpression of AURKA and inactivation of BRCA1 and BRCA2 cooperate during tumor development and progression. The F31I polymorphism in AURKA has been associated 1416 Received 2/19/07; revised 4/10/07; accepted 4/23/07. Grant support: Breast Cancer Research Foundation, U.S. Army Medical Research and Materiel Command grant W81XWH-04-1-0588, and Mayo Clinic Breast Cancer Specialized Program of Research Excellence grant P50-CA116201 (F.J. Couch); Cancer Care Ontario and RFA CA-95-003 as part of the National Cancer Institute Breast Cancer Family Registries (I.L. Andrulis); Canadian Institute for Health Research through the INHERIT BRCAs program (J. Simard); Dutch Cancer Society grant UL2001-2471 (P. Devilee); Academy of Finland (110663), Finnish Cancer Society, Helsinki University Central Hospital Research Fund, and Sigrid Juselius Fund (H. Nevanlinna); Deutsches Krebsforschungszentrum Heidelberg (U. Hamann); NIH grants R01-CA74415 (S.L. Neuhausen) and R01-CA083855 and R01-CA102776 (T.R. Rebbeck); The Programme Hospitalier de Recherche Clinique AOR01082 (D. Stoppa-Lyonnet and O. Sinilnikova); Komen Foundation BCTR 0601361 and WeissenbachSouthworth-Niehaus Research Fund (K. Offitt); The German Cancer Aid grant 107054 and Center for Molecular Medicine Cologne grant TV 93 (R. Schmutzler). A General Clinic Research Center grant from the NIH (M01 RR00043) awarded to the City of Hope National Cancer Epidemiol Biomarkers Prev 2007;16(7). July 2007 Center supports in part the collection and management of the Hereditary Cancer Registry (J. Weitzel). kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council, and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. D.F. Easton is a principal research fellow of Cancer Research UK. EMBRACE and A. Antoniou are funded by an award from Cancer Research UK. 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. Requests for reprints: Fergus J. Couch, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-284-3623; Fax: 507-266-0824. E-mail: Couch.fergus@mayo.edu Copyright D 2007 American Association for Cancer Research. doi:10.1158/1055-9965.EPI-07-0129 with breast cancer risk in the homozygous state in prior studies. We evaluated whether the AURKA F31I polymorphism modifies breast cancer risk in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2. Consortium of Investigators of Modifiers of BRCA1/2 was established to provide sufficient statistical power through increased numbers of mutation carriers to identify polymorphisms that act as modifiers of cancer risk and can refine breast cancer risk estimates in BRCA1 and BRCA2 mutation carriers. A total of 4,935 BRCA1 and 2,241 BRCA2 mutation carriers and 11 individuals carrying both BRCA1 and BRCA2 mutations was genotyped for F31I. Overall, homozygosity for the 31I allele was not significantly associated with breast cancer risk in BRCA1 and BRCA2 carriers combined [hazard ratio (HR), 0.91; 95% confidence interval (95% CI), 0.77-1.06]. Similarly, no significant association was seen in BRCA1 (HR, 0.90; 95% CI, 0.75-1.08) or BRCA2 carriers (HR, 0.93; 95% CI, 0.67-1.29) or when assessing the modifying effects of either bilateral prophylactic oophorectomy or menopausal status of BRCA1 and BRCA2 carriers. In summary, the F31I polymorphism in AURKA is not associated with a modified risk of breast cancer in BRCA1 and BRCA2 carriers. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1416–21)