[Mutations of the androgen receptor gene a possible role in prostate cancer]

Abstract

Prostate cancer is the second most frequent cancer in men, and the first after 75 years of age. It is androgen dependent and modifications of the androgen receptor (AR) could therefore be involved in its apparition, progression and evolution towards a stage of androgen independence which always occurs. Mutations of the AR have indeed been described. Some result in a more active receptor (constitutive mutations, amplification of the AR gene expression, prevalence of shorter alleles in exon 1) and could therefore be responsible for the progression of the disease in the absence of androgens or the increased cancer risk in some populations. Other mutations, in the ligand binding domain, modify the AR specificity resulting in its activation by weak androgens or even antiandrogens, progestagens or estradiol. These mutations could also explain why prostate cancer progresses in the absence of androgens. On the other hand, mutations resulting in androgen insensitivity could explain why a significant number of prostate cancer remain latent and never develop into an aggressive tumor. Finally, exon 1 polymorphism could be used as a prognostic marker, as it has been shown that the shorter alleles result in a more active AR and are predominant in populations at higher risk for prostate cancer. At any rate, even if AR mutations may be more frequent than initially thought, they remain rare and their significance remains to be determined.