Sequence variants of estrogen receptor beta and risk of prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium.
BACKGROUND
Estrogen receptor beta (ESR2) may play a role in modulating prostate carcinogenesis through the regulation of genes related to cell proliferation and apoptosis.


METHODS
We conducted nested case-control studies in the Breast and Prostate Cancer Cohort Consortium (BPC3) that pooled 8,323 prostate cancer cases and 9,412 controls from seven cohorts. Whites were the predominant ethnic group. We characterized genetic variation in ESR2 by resequencing exons in 190 breast and prostate cancer cases and genotyping a dense set of single nucleotide polymorphisms (SNP) spanning the locus in a multiethnic panel of 349 cancer-free subjects. We selected four haplotype-tagging SNPs (htSNP) to capture common ESR2 variation in Whites; these htSNPs were then genotyped in all cohorts. Conditional logistic regression models were used to assess the association between sequence variants of ESR2 and the risk of prostate cancer. We also investigated the effect modification by age, body mass index, and family history, as well as the association between sequence variants of ESR2 and advanced-stage (>or=T3b, N1, or M1) and high-grade (Gleason sum >or=8) prostate cancer, respectively.


RESULTS
The four tag SNPs in ESR2 were not significantly associated with prostate cancer risk, individually. The global test for the influence of any haplotype on the risk of prostate cancer was not significant (P = 0.31). However, we observed that men carrying two copies of one of the variant haplotypes (TACC) had a 1.46-fold increased risk of prostate cancer (99% confidence interval, 1.06-2.01) compared with men carrying zero copies of this variant haplotype. No SNPs or haplotypes were associated with advanced stage or high grade of prostate cancer.


CONCLUSIONS
In our analysis focused on genetic variation common in Whites, we observed little evidence for any substantial association of inherited variation in ESR2 with risk of prostate cancer. A nominally significant (P < 0.01) association between the TACC haplotype and prostate cancer risk under the recessive model could be a chance finding and, in any event, would seem to contribute only slightly to the overall burden of prostate cancer.
Chen
Yen-Ching
YC
Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115, USA. karen.chen@channing.harvard.edu
Kraft
Peter
P
Bretsky
Philip
P
Ketkar
Shamika
S
Hunter
David J
DJ
Albanes
Demetrius
D
Altshuler
David
D
Andriole
Gerald
G
Berg
Christine D
CD
Boeing
Heiner
H
Burtt
Noel
N
Bueno-de-Mesquita
Bas
B
Cann
Howard
H
Canzian
Federico
F
Chanock
Stephen
S
Dunning
Alison
A
Feigelson
Heather S
HS
Freedman
Matthew
M
Gaziano
J Michael
JM
Giovannucci
Edward
E
Sánchez
Maria-Jose
MJ
Haiman
Christopher A
CA
Hallmans
Göran
G
Hayes
Richard B
RB
Henderson
Brian E
BE
Hirschhorn
Joel
J
Kaaks
Rudolf
R
Key
Timothy J
TJ
Kolonel
Laurence N
LN
LeMarchand
Loic
L
Ma
Jing
J
Overvad
Kim
K
Palli
Domenico
D
Pharaoh
Paul
P
Pike
Malcolm
M
Riboli
Eliot
E
Rodriguez
Carmen
C
Setiawan
V Wendy
VW
Stampfer
Meir
M
Stram
Daniel O
DO
Thomas
Gilles
G
Thun
Michael J
MJ
Travis
Ruth C
RC
Virtamo
Jarmo
J
Trichopoulou
Antonia
A
Wacholder
Sholom
S
Weinstein
Stephanie J
SJ
D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D015331:Cohort Studies; D047629:Estrogen Receptor beta / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D018570:Risk Assessment; D017422:Sequence Analysis, DNA / Q000379:methods*
D047629:Estrogen Receptor beta