Androgen and vitamin D receptor gene polymorphisms: the long and short of prostate cancer risk.

Abstract

In this issue of the Journal, in a study of candidate genes and prostate cancer susceptibility, Ingles et al. ( 1) report on the association of polymorphisms in the genes encoding the androgen receptor (AR) and the vitamin D receptor (VDR) with the risk of prostate cancer. The polymorphisms, discussed in detail below, both result from variations in length of nucleotide repeats; the AR polymorphism is due to an expansion of CAG codons, whereas the VDR polymorphism is due to an increased number of adenosines in a poly-A tract. The short AR alleles (with <20 CAG repeats) were associated with an adjusted odds ratio of 2.1-fold greater risk of prostate cancer, and the long VDR alleles (with poly-A of o18) were associated with a 4.6-fold greater risk. In both cases, the at-risk genotypes were more strongly associated with advanced disease than with localized disease limited to the prostate. These polymorphisms are among the strongest genetic risk factors found yet for prostate cancer and are therefore of great potential significance. It should be emphasized, however, that the variant alleles under study are distributed among the normal population and that a polymorphism does not necessarily cause the cancer but is merely associated with increased risk of having the cancer. Given the importance of androgens for prostate growth, one might expect that a modification in the AR could cause a genetic effect on prostate cancer risk; the VDR, however, is another story, and the relationship of vitamin D to the prostate and prostate cancer has been recognized only recently (2-6). However, the AR and VDR have many similarities. Both are members of the steroid‐thyroid‐retinoid receptor superfamily of hormone-dependent nuclear transcription factors. The AR gene has been localized to the proximal long arm of the X chromosome and the VDR to chromosome 12q14. The hormonal ligands for both receptors circulate as prehormones, testosterone and 25hydroxyvitamin D, respectively. Both prehormones have low hormonal activity but can be converted to the highly active form by specific enzymes, 5a-reductase to produce 5a-dihydrotestosterone (DHT) and 1a-hydroxylase to produce 1a,25-dihydroxyvitamin D3 (calcitriol), respectively. In both cases, the nuclear receptor is essential for hormone action, and inactivating mutations in the receptors can cause hormone-resistant syndromes, androgen insensitivity syndrome, and hereditary vitamin D-resistant rickets. Both hormones act via their cognate receptors to regulate cell proliferation; DHT stimulates and calcitriol inhibits prostate cell growth. Also, both hormones stimulate secretion of prostate-specific antigen ( 5). The study by