title: CYP17 genetic variation and risk of breast and prostate cancer from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3).
abstract: CYP17 encodes cytochrome p450c17alpha, which mediates activities essential for the production of sex steroids. Common germ line variation in the CYP17 gene has been related to inconsistent results in breast and prostate cancer, with most studies focusing on the nonsynonymous single nucleotide polymorphism (SNP) T27C (rs743572). We comprehensively characterized variation in CYP17 by direct sequencing of exons followed by dense genotyping across the 58 kb region around CYP17 in five racial/ethnic populations. Two blocks of strong linkage disequilibrium were identified and nine haplotype-tagging SNPs, including T27C, were chosen to predict common haplotypes (R(h)(2) >or= 0.85). These haplotype-tagging SNPs were genotyped in 8,138 prostate cancer cases and 9,033 controls, and 5,333 breast cancer cases and 7,069 controls from the Breast and Prostate Cancer Cohort Consortium. We observed borderline significant associations with prostate cancer for rs2486758 [TC versus TT, odds ratios (OR), 1.07; 95% confidence intervals (95% CI), 1.00-1.14; CC versus TT, OR, 1.09; 95% CI, 0.95-1.26; P trend=0.04] and rs6892 (AG versus AA, OR, 1.08; 95% CI, 1.00-1.15; GG versus AA, OR, 1.11; 95% CI, 0.95-1.30; P trend=0.03). We also observed marginally significant associations with breast cancer for rs4919687 (GA versus GG, OR, 1.04; 95% CI, 0.97-1.12, AA versus GG, OR, 1.17; 95% CI, 1.03-1.34; P trend=0.03) and rs4919682 (CT versus CC, OR, 1.04; 95% CI, 0.97-1.12; TT versus CC, OR, 1.16; 95% CI, 1.01-1.33; P trend=0.04). Common variation at CYP17 was not associated with circulating sex steroid hormones in men or postmenopausal women. Our findings do not support the hypothesis that common germ line variation in CYP17 makes a substantial contribution to postmenopausal breast or prostate cancer susceptibility.
authors.affiliation: Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033, USA. vsetiawa@usc.edu
authors.forename: Veronica Wendy
authors.initials: VW
authors.lastname: Setiawan
authors.forename: Fredrick R
authors.initials: FR
authors.lastname: Schumacher
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Stram
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Göran
authors.initials: G
authors.lastname: Berglund
authors.forename: Julie
authors.initials: J
authors.lastname: Buring
authors.forename: Eugenia E
authors.initials: EE
authors.lastname: Calle
authors.forename: Françoise
authors.initials: F
authors.lastname: Clavel-Chapelon
authors.forename: David G
authors.initials: DG
authors.lastname: Cox
authors.forename: J Michael
authors.initials: JM
authors.lastname: Gaziano
authors.forename: Susan E
authors.initials: SE
authors.lastname: Hankinson
authors.forename: Richard B
authors.initials: RB
authors.lastname: Hayes
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.forename: Joel
authors.initials: J
authors.lastname: Hirschhorn
authors.forename: Robert
authors.initials: R
authors.lastname: Hoover
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kaaks
authors.forename: Laurence N
authors.initials: LN
authors.lastname: Kolonel
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
authors.forename: Jakob
authors.initials: J
authors.lastname: Linseisen
authors.forename: Eiliv
authors.initials: E
authors.lastname: Lund
authors.forename: Carmen
authors.initials: C
authors.lastname: Navarro
authors.forename: Kim
authors.initials: K
authors.lastname: Overvad
authors.forename: Domenico
authors.initials: D
authors.lastname: Palli
authors.forename: Petra H M
authors.initials: PH
authors.lastname: Peeters
authors.forename: Malcolm C
authors.initials: MC
authors.lastname: Pike
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.forename: Meir J
authors.initials: MJ
authors.lastname: Stampfer
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thun
authors.forename: Ruth
authors.initials: R
authors.lastname: Travis
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Trichopoulos
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Regina G
authors.initials: RG
authors.lastname: Ziegler
authors.forename: Heather
authors.initials: H
authors.lastname: Spencer Feigelson
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D003299:Cooperative Behavior; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics*; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism
chemical_list: D012739:Gonadal Steroid Hormones; D013254:Steroid 17-alpha-Hydroxylase