title: A systematic assessment of common genetic variation in CYP11A and risk of breast cancer.
abstract: 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 (> or =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 (> or =5% frequency) in these regions with high probability (average R(h)(2) = 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.
authors.affiliation: Departments of Preventive Medicine and Urology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA. vsetiawa@usc.edu
authors.forename: Veronica Wendy
authors.initials: VW
authors.lastname: Setiawan
authors.forename: Iona
authors.initials: I
authors.lastname: Cheng
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Stram
authors.forename: Elena
authors.initials: E
authors.lastname: Giorgi
authors.forename: Malcolm C
authors.initials: MC
authors.lastname: Pike
authors.forename: David
authors.initials: D
authors.lastname: Van Den Berg
authors.forename: Loreall
authors.initials: L
authors.lastname: Pooler
authors.forename: Noel P
authors.initials: NP
authors.lastname: Burtt
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Joel
authors.initials: J
authors.lastname: Hirschhorn
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
mesh_terms: D001943:Breast Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D018567:Breast Neoplasms, Male / Q000453:epidemiology* / Q000235:genetics*; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics*; D015331:Cohort Studies; D005006:Ethnicity / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D044469:Racial Groups / Q000235:genetics; D012016:Reference Values; D018570:Risk Assessment; D014481:United States / Q000453:epidemiology
chemical_list: D002786:Cholesterol Side-Chain Cleavage Enzyme