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A Systematic Assessment of Common Genetic Variation in CYP11A and Risk of Breast Cancer

Departments of ¹ Preventive Medicine and ² Urology, Keck School of Medicine, University of Southern California, Los Angeles, California; ³ Department of Epidemiology and Biostatistics and Center of Human Genetics, University of California, San Francisco, San Francisco, California; ⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Departments of ⁵ Genetics, ⁶ Medicine, and ⁷ Pediatrics, Harvard Medical School; ⁸ Department of Molecular Biology and ⁹ Diabetes Unit, Massachusetts General Hospital; ¹⁰ Division of Genetics and Endocrinology, Children's Hospital and Department of Pediatrics, Boston, Massachusetts; and ¹¹ Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii

Requests for reprints: Veronica Wendy Setiawan, Department of Preventive Medicine, USC/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Room 4425, Los Angeles, CA 90033. Phone: 323-865-0411; Fax: 323-865-0127; E-mail: vsetiawa{at}usc.edu.

CYP11A catalyzes the rate-limiting step in the biosynthesis of sex-steroid hormones. In this study, we employed a systematic approach that involved gene resequencing and a haplotype-based analysis to investigate the relationship between common variation in CYP11A and breast cancer risk among African-Americans, Latinas, Japanese-Americans, Native Hawaiians, and Whites in the Multiethnic Cohort Study. Resequencing in a multiethnic panel of 95 advanced breast cancer cases revealed no common missense variant (5% frequency). Common haplotype patterns were assessed by genotyping 36 densely spaced single nucleotide polymorphisms (SNPs) spanning 67 kb of the CYP11A locus in a multiethnic panel of subjects (n = 349; 1 SNP/1.86 kb on average). We identified one to two regions of strong linkage disequilibrium in these populations. Twelve tagging SNPs were selected to predict the common haplotypes (5% frequency) in these regions with high probability (average R_h² = 0.94) and were examined in a breast cancer case-control study in the Multiethnic Cohort Study (1,615 cases and 1,962 controls). A global test for differences in risk according to common haplotypes over the locus was statistically significant (P = 0.006), as were associations with haplotypes in each block (block 1 global test, P = 0.008; haplotype 1D, effect per haplotype copy, odds ratios, 1.23; 95% confidence interval, 1.03–1.48) and block 2 (global test, P = 0.016; haplotype 2F odds ratios, 1.52; 95% confidence interval, 1.15–2.01). These haplotypes were most common in Japanese-Americans and Native Hawaiians, followed by Whites then Latinas, and were rare in African-Americans (<5% frequency); the haplotype effects on risk across each group were homogeneous. Based on these findings, CYP11A deserves further consideration as a candidate breast cancer susceptibility gene. (Cancer Res 2006; 66(24): 12019-25)

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