||5R03CA092706-02 Interpret this number
||Fred Hutchinson Cancer Research Center
||Androgen Pathway and Genetic Risk of Prostate Cancer
DESCRIPTION (provided by applicant):
Prostate cancer is the most common internal malignancy and second leading
cause of cancer mortality among U.S. men. The androgen pathway in the prostate
is believed to mediate carcinogenesis by stimulating cell proliferation,
thereby increasing the opportunity for random genetic errors to accumulate and
give rise to a malignant phenotype. Androgen activity in the prostate is
regulated by enzymes and transcription factors that are encoded by highly
polymorphic genes. We propose to test the hypothesis that the possession of
certain variant alleles in genes in the androgen pathway increases a man's
risk of prostate cancer. Specifically the genes of interest encode: (1)
steroid 5 alpha-reductase type II (SRD5A2), which bioactivates androgens in
the prostate; (2) androgen receptor (AR), an androgen-dependent nuclear
transcription factor; and (3) prostate-specific antigen (PSA), a serine
protease transactivated by AR that cleaves and reverses the growth-inhibitory
effects of insulin-like growth factor binding protein-3 (IGFBP-3). The SRDSA2,
AR, and PSA genes each encode products that mediate androgen stimulation of
the prostate. Furthermore, each gene possesses a polymorphism with
demonstrated functionality and sufficient allelic frequency to explain a
substantial proportion of prostate cancer in the U.S. population.
We propose to conduct a nested case-control study within the Cardiovascular
Health Study (CHS) to test the hypothesis that possession of variant alleles
in the SRDSA2, AR, and PSA genes, individually and in combination, increases a
man's risk of prostate cancer. CHS is a multicenter cohort study in older
adults that has prospectively collected detailed interview data and blood
samples since 1989. Cases will be approximately 210 CHS male participants
diagnosed with prostate cancer after enrollment and through 1999. Controls
will be 420 CHS male participants, frequency matched to cases by age and race,
who were not diagnosed with prostate cancer through 1999 and who were alive as
of the date of diagnosis of the matched case. We propose to conduct laboratory
analysis of DNA samples provided by CHS to determine the presence of variant
alleles among cases and controls, and statistical analysis to assess whether
SRD5A2, AR, and PSA genotypes influence the risk of prostate cancer. The
identification and confirmation of high-risk genetic profiles for prostate
cancer could enable better screening and potential preventive interventions
aimed at the gene products.
Genetic Susceptibility to Prostate Cancer: Prostate-specific Antigen and its Interaction with the Androgen Receptor (United States).
, Edwards K.L.
, Fitzpatrick A.L.
, Srinouanprachanh S.L.
, Farin F.M.
, Monks S.A.
, Kronmal R.A.
, Eaton D.L.
Cancer causes & control : CCC, 2006 Mar; 17(2), p. 187-97.