A systematic assessment of common genetic variation in CYP11A and risk of breast cancer.
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.
Setiawan
Veronica Wendy
VW
Departments of Preventive Medicine and Urology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA. vsetiawa@usc.edu
Cheng
Iona
I
Stram
Daniel O
DO
Giorgi
Elena
E
Pike
Malcolm C
MC
Van Den Berg
David
D
Pooler
Loreall
L
Burtt
Noel P
NP
Le Marchand
Loic
L
Altshuler
David
D
Hirschhorn
Joel
J
Henderson
Brian E
BE
Haiman
Christopher A
CA
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
D002786:Cholesterol Side-Chain Cleavage Enzyme