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The Androgen Receptor CAG Repeat and Prostate Cancer Risk

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The androgen receptor (AR) gene comprises eight exons located at chromosome Xq11-12 and encodes an mRNA transcript of approx 11 kb (1 5 ). Situated within exon 1 of the AR gene is a polymorphic CAG trinucleotide repeat, which encodes a polyglutamine (poly-Q) tract of variable length in the N-terminal domain of the AR protein. The normal size range of this poly-Q tract is between 6 and 39 repeats (6 ,7 ). The gene is considered a good candidate to play a role in the etiology of prostate cancer because of this variation and the well-documented importance of AR signaling in prostate development and tumor growth. Although earlier family studies failed to link prostate cancer to the AR locus, the CAG repeat variations of this locus have been considered to play a modifying role in prostate cancer risk (as apposed to causing it). The AR on the X chromosome is, furthermore, thought to contribute to the increased brother/brother vs father/son risk associations observed in several studies (8 10 ). More recently, however, linkage to the AR locus (LOD score 3.06, p =0.00053) was observed in 254 families if, and only if, Gleason score, age of onset, male-to-male transmission, and/or number of affected first-degree family members were included as covariates (10 ).
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