CYP19A1 genetic variation in relation to prostate cancer risk and circulating sex hormone concentrations in men from the Breast and Prostate Cancer Cohort Consortium.
Sex hormones, particularly the androgens, are important for the growth of the prostate gland and have been implicated in prostate cancer carcinogenesis, yet the determinants of endogenous steroid hormone levels remain poorly understood. Twin studies suggest a heritable component for circulating concentrations of sex hormones, although epidemiologic evidence linking steroid hormone gene variants to prostate cancer is limited. Here we report on findings from a comprehensive study of genetic variation at the CYP19A1 locus in relation to prostate cancer risk and to circulating steroid hormone concentrations in men by the Breast and Prostate Cancer Cohort Consortium (BPC3), a large collaborative prospective study. The BPC3 systematically characterized variation in CYP19A1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNP) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,166 prostate cancer cases and 9,079 study-, age-, and ethnicity-matched controls. CYP19A1 htSNPs, two common missense variants and common haplotypes were not significantly associated with risk of prostate cancer. However, several htSNPs in linkage disequilibrium blocks 3 and 4 were significantly associated with a 5% to 10% difference in estradiol concentrations in men [association per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 1 x 10(-5)], and with inverse, although less marked changes, in free testosterone concentrations. These results suggest that although germline variation in CYP19A1 characterized by the htSNPs produces measurable differences in sex hormone concentrations in men, they do not substantially influence risk of prostate cancer.
Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Richard Doll Building, Oxford, United Kingdom. ruth.travis@ceu.ox.ac.uk
Ruth C
RC
Travis
Fredrick
F
Schumacher
Joel N
JN
Hirschhorn
Peter
P
Kraft
Naomi E
NE
Allen
Demetrius
D
Albanes
Goran
G
Berglund
Sonja I
SI
Berndt
Heiner
H
Boeing
H Bas
HB
Bueno-de-Mesquita
Eugenia E
EE
Calle
Stephen
S
Chanock
Alison M
AM
Dunning
Richard
R
Hayes
Heather Spencer
HS
Feigelson
J Michael
JM
Gaziano
Edward
E
Giovannucci
Christopher A
CA
Haiman
Brian E
BE
Henderson
Rudolf
R
Kaaks
Laurence N
LN
Kolonel
Jing
J
Ma
Laudina
L
Rodriguez
Elio
E
Riboli
Meir
M
Stampfer
Daniel O
DO
Stram
Michael J
MJ
Thun
Anne
A
Tjønneland
Dimitrios
D
Trichopoulos
Paolo
P
Vineis
Jarmo
J
Virtamo
Loïc
L
Le Marchand
David J
DJ
Hunter
D000368:Aged; D001141:Aromatase / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D012739:Gonadal Steroid Hormones / Q000097:blood* / Q000235:genetics; D006801:Humans; D008297:Male; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000097:blood* / Q000201:enzymology / Q000235:genetics*; D012307:Risk Factors
D012739:Gonadal Steroid Hormones; D001141:Aromatase