Polymorphic CAG and GGN repeat lengths in the androgen receptor gene and prostate cancer risk: A population-based case-control study in China

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 i n the CAG repeat length, this polymorphism has been suggested to explain pa rt of the substantial racial difference in prostate cancer risk, We conduct ed a population-based case-control study in China to investigate whether CA G and other polymorphisms of the AR gene are associated with clinically sig nificant prostate cancer in this low-risk population. Genomic DNA from 190 prostate cancer patients and 304 healthy controls was used for direct seque ncing to evaluate the relationship of CAG and GGN (polyglycine) repeat leng th 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 r atio, 1.65; 95% confidence interval, 1.14-2.39), compared with men with a C AG repeat length of 23 or longer. For the GGN tract (GGT(3)GGG(1)GGT(2)GGC( n)), 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 GG N repeat length shorter than 23 had a 12% increased risk of prostate cancer (95% confidence interval, 0.71-1.78), compared with those with greater tha n or equal to 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 populati on, a shorter CAG repeat length confers a higher risk of clinically signifi cant prostate cancer. These results imply that CAG repeat length can potent ially serve as a useful marker to identify a subset of individuals at highe r 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 tha t interact with the polyglutamine region of the AR gene to alter AR functio n and modulate prostate cancer risk is an important area for future researc h.