A large study of androgen receptor germline variants and their relation to sex hormone levels and prostate cancer risk. Results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium.
BACKGROUND
Androgens are key regulators of prostate gland maintenance and prostate cancer growth, and androgen deprivation therapy has been the mainstay of treatment for advanced prostate cancer for many years. A long-standing hypothesis has been that inherited variation in the androgen receptor (AR) gene plays a role in prostate cancer initiation. However, studies to date have been inconclusive and often suffered from small sample sizes.


OBJECTIVE
We investigated the association of AR sequence variants with circulating sex hormone levels and prostate cancer risk in 6058 prostate cancer cases and 6725 controls of Caucasian origin within the Breast and Prostate Cancer Cohort Consortium. We genotyped a highly polymorphic CAG microsatellite in exon 1 and six haplotype tagging single nucleotide polymorphisms and tested each genetic variant for association with prostate cancer risk and with sex steroid levels.


RESULTS
We observed no association between AR genetic variants and prostate cancer risk. However, there was a strong association between longer CAG repeats and higher levels of testosterone (P = 4.73 x 10(-5)) and estradiol (P = 0.0002), although the amount of variance explained was small (0.4 and 0.7%, respectively).


CONCLUSIONS
This study is the largest to date investigating AR sequence variants, sex steroid levels, and prostate cancer risk. Although we observed no association between AR sequence variants and prostate cancer risk, our results support earlier findings of a relation between the number of CAG repeats and circulating levels of testosterone and estradiol.
Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
Sara
S
Lindström
Jing
J
Ma
David
D
Altshuler
Edward
E
Giovannucci
Elio
E
Riboli
Demetrius
D
Albanes
Naomi E
NE
Allen
Sonja I
SI
Berndt
Heiner
H
Boeing
H Bas
HB
Bueno-de-Mesquita
Stephen J
SJ
Chanock
Alison M
AM
Dunning
Heather Spencer
HS
Feigelson
J Michael
JM
Gaziano
Christopher A
CA
Haiman
Richard B
RB
Hayes
Brian E
BE
Henderson
David J
DJ
Hunter
Rudolf
R
Kaaks
Laurence N
LN
Kolonel
Loic
L
Le Marchand
Carmen
C
Martínez
Kim
K
Overvad
Afshan
A
Siddiq
Meir
M
Stampfer
Pär
P
Stattin
Daniel O
DO
Stram
Michael J
MJ
Thun
Dimitrios
D
Trichopoulos
Rosario
R
Tumino
Jarmo
J
Virtamo
Stephanie J
SJ
Weinstein
Meredith
M
Yeager
Peter
P
Kraft
Matthew L
ML
Freedman
D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics; D002277:Carcinoma / Q000097:blood / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000502:physiology; D012739:Gonadal Steroid Hormones / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D054547:National Cancer Institute (U.S.); D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics*; D012306:Risk; D018911:Trinucleotide Repeats / Q000235:genetics; D014481:United States
C410798:AR protein, human; D012739:Gonadal Steroid Hormones; D011944:Receptors, Androgen