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Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20852-7234 [A. W. H.]; Shanghai Cancer Institute, Shanghai, China 200032 [Y-T. G., J. D.]; University of Rochester, Rochester, New York, 14642 [G. W., X. W., Y-L. C., C. C.]; Armed Forces Institute of Pathology, Washington, D.C. 20306 [I. A. S., F. K. M.]; and University of Rouen, 76031 Rouen, France [J. B.]
The length of the polymorphic CAG trinucleotide repeat in the
polyglutamine region of the androgen receptor
(AR) gene is inversely correlated with the
transactivation function of the AR. Because increased androgenic
activity has been linked to prostate cancer and because an ethnic
variation exists in the CAG repeat length, this polymorphism has been
suggested to explain part of the substantial racial difference in
prostate cancer risk. We conducted a population-based case-control
study in China to investigate whether CAG and other polymorphisms of
the AR gene are associated with clinically significant
prostate cancer in this low-risk population. Genomic DNA from 190
prostate cancer patients and 304 healthy controls was used for direct
sequencing to evaluate the relationship of CAG and GGN (polyglycine)
repeat length in the AR gene. Relative to western men,
our study subjects had a longer CAG repeat length, with a median of 23
and only 10% of the subjects having a CAG repeat length shorter than
20. Men with a CAG repeat length shorter than 23 (median length)
had a 65% increased risk of prostate cancer (odds ratio, 1.65;
95% confidence interval, 1.14–2.39), compared with men with a CAG
repeat length of 23 or longer. For the GGN tract
(GGT3GGG1GGT2GGCn),
based on the sequencing results from 481 samples, we are the first to
show that although GGC regions in the polyglycine tract are highly
variable, there are no mutations or polymorphisms in the GGT and GGG
regions. More than 72% of the subjects had a GGN repeat length of 23,
and those with a GGN repeat length shorter than 23 had a 12% increased
risk of prostate cancer (95% confidence interval, 0.71–1.78),
compared with those with 
23 GGN repeats. Our study not only confirms
that Chinese men do have a longer CAG repeat length than western men
but also represents the first population-based study to show that even
in a very low-risk population, a shorter CAG repeat length confers a
higher risk of clinically significant prostate cancer. These results
imply that CAG repeat length can potentially serve as a useful marker
to identify a subset of individuals at higher risk of developing
clinically significant prostate cancer. Larger studies are needed to
evaluate the combined effect of CAG and GGN repeats. Because of the
significance of AR in prostate cancer, investigation of factors that
interact with the polyglutamine region of the AR gene to
alter AR function and modulate prostate cancer risk is an important
area for future research.
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