Genetic variation in the HSD17B1 gene and risk of prostate cancer.
Steroid hormones are believed to play an important role in prostate carcinogenesis, but epidemiological evidence linking prostate cancer and steroid hormone genes has been inconclusive, in part due to small sample sizes or incomplete characterization of genetic variation at the locus of interest. Here we report on the results of a comprehensive study of the association between HSD17B1 and prostate cancer by the Breast and Prostate Cancer Cohort Consortium, a large collaborative study. HSD17B1 encodes 17beta-hydroxysteroid dehydrogenase 1, an enzyme that converts dihydroepiandrosterone to the testosterone precursor Delta5-androsterone-3beta,17beta-diol and converts estrone to estradiol. The Breast and Prostate Cancer Cohort Consortium researchers systematically characterized variation in HSD17B1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNPs) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,290 prostate cancer cases and 9,367 study-, age-, and ethnicity-matched controls. We found no evidence that HSD17B1 htSNPs (including the nonsynonymous coding SNP S312G) or htSNP haplotypes were associated with risk of prostate cancer or tumor stage in the pooled multiethnic sample or in U.S. and European whites. Analyses stratified by age, body mass index, and family history of disease found no subgroup-specific associations between these HSD17B1 htSNPs and prostate cancer. We found significant evidence of heterogeneity in associations between HSD17B1 haplotypes and prostate cancer across ethnicity: one haplotype had a significant (p < 0.002) inverse association with risk of prostate cancer in Latinos and Japanese Americans but showed no evidence of association in African Americans, Native Hawaiians, or whites. However, the smaller numbers of Latinos and Japanese Americans in this study makes these subgroup analyses less reliable. These results suggest that the germline variants in HSD17B1 characterized by these htSNPs do not substantially influence the risk of prostate cancer in U.S. and European whites.
Kraft
Peter
P
Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
Pharoah
Paul
P
Chanock
Stephen J
SJ
Albanes
Demetrius
D
Kolonel
Laurence N
LN
Hayes
Richard B
RB
Altshuler
David
D
Andriole
Gerald
G
Berg
Christine
C
Boeing
Heiner
H
Burtt
Noel P
NP
Bueno-de-Mesquita
Bas
B
Calle
Eugenia E
EE
Cann
Howard
H
Canzian
Federico
F
Chen
Yen-Ching
YC
Crawford
David E
DE
Dunning
Alison M
AM
Feigelson
Heather S
HS
Freedman
Matthew L
ML
Gaziano
John M
JM
Giovannucci
Ed
E
Gonzalez
Carlos Alberto
CA
Haiman
Christopher A
CA
Hallmans
Goran
G
Henderson
Brian E
BE
Hirschhorn
Joel N
JN
Hunter
David J
DJ
Kaaks
Rudolf
R
Key
Timothy
T
Le Marchand
Loic
L
Ma
Jing
J
Overvad
Kim
K
Palli
Domenico
D
Pike
Malcolm C
MC
Riboli
Elio
E
Rodriguez
Carmen
C
Setiawan
Wendy V
WV
Stampfer
Meir J
MJ
Stram
Daniel O
DO
Thomas
Gilles
G
Thun
Michael J
MJ
Travis
Ruth
R
Trichopoulou
Antonia
A
Virtamo
Jarmo
J
Wacholder
Sholom
S
D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics*; D000368:Aged; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000208:ethnology / Q000235:genetics*; D012306:Risk; D012307:Risk Factors
D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase