peat polymorphism in the 3'-untranslated region. Constitutional DNA missense substitutions are identified below the gene in the single-letter amino acid code.
tein, others resulted in either increases or decreases in enzyme kinetics. One in particular, an alanine-to-threonine substitution at codon 49 (A49T), resulted in a substantial increase in enzyme activity. Although uncommon in healthy control men, the Reichardt group assessed its possible role in prostate cancer etiology in a multiracial nested case-control study because of its substantial impact in vitro. In both African-American and Latino men, the A49T polymorphism was associated with substantial increases in prostate cancer risk, especially for advanced disease at presentation [relative risk (RR) = 1.5 for localized and 7.1 for advanced disease, respectively, in African Americans, p = 0.001 for the latter association; RR = 1.7 for localized and 3.6 for advanced disease, respectively, among Latinos, p = 0.043 for the latter association]. The contribution of the A49T mutation in prostate cancer predisposition worldwide is uncertain; increased incidence of the A49T mutation has been reported in Italian prostate cancer patients,48 while no difference between prostate cancer and control patients was reported in Fin-
This same group has investigated the frequency of somatic mutations in SRD5A2 in tissue from prostate cancer patients.50 By far, the most common de novo mutation in prostate cancer tissue in the SRD5A2 gene is the same A49T variant associated with such a substantial increase in prostate cancer risk in constitutional DNA.
Finally, the work by Reichardt, Ross, and their colleagues on 5a-reductase hormonal indices and genotypes led directly to an ongoing national trial to evaluate chemopreventive efficacy of the 5a-reductase inhibitor finasteride on prostate cancer risk in 18,000 healthy men with normal PSA levels.51 Importantly, Reichardt et al.47 demonstrated that inhibition of 5a-reductase activity in vitro depends strongly on SRD5A2 genotype. For example, finasteride displays 11- to 7-fold lower affinity for the A49T mutant enzyme than for the wild-type protein in vitro. Therefore, if finasteride proves efficacious in preventing prostate cancer in this trial, the degree of protection may vary substantially according to constitutional polymorphic variation in the SRD5A2 gene, which may eventually allow better targeting for such chemopreventive interventions.
The SRD5A2 gene association with prostate cancer risk has supplied a useful paradigm to systematically investigate other candidate genes for prostate cancer, i.e., beginning with rigorous sequencing of the gene among healthy individuals with extreme levels of biochemical correlates of the protein product of the gene, to identify polymorphic variants and their frequencies across racial/ethnic groups; then, proceeding to assess the functional significance of each genetic variant in vitro; for those of interest, to then conduct an appropriate epidemiological study to determine the strength of any association between specific variants and disease risk; to determine whether somatic mutations of this variant occur in the course of disease progression; and, if possible, to use this information to design and implement prevention intervention strategies.
The AR gene is reviewed in Chapter 16. The gene is located on the X chromosome and has a structure similar to other steroid hormone receptor genes, with a DNA-binding domain, a ligand-binding domain, and a transcription-modulatory domain.52 Given the multiple functions of the receptor in androgen activity in the prostate, it is a strong candidate gene in prostate cancer etiology. Coetzee and Ross53 noted that expansion of a trinucleotide (CAG)n repeat polymorphism in exon 1 (the transacti-vation domain) of the gene caused a rare adult-onset motor neuron disease, spinal and bulbar muscular atrophy, or Kennedy's disease.53 Men with this genetic disorder have evidence of reduced androgen activity, even though androgen binding by their ARs appears to be nor-mal.54 Coetzee and Ross53 hypothesized that if there is suboptimal transactivation in the expanded CAG repeat range (>36 CAGs) associated with Kennedy's disease, there might also be a range of androgen transactivation within the normal range of repeats (~8-33 CAGs); thus, men in the higher part of the range might have less androgen transactivation than men in the lower part of the range. Their hypothesis further predicted that men with relatively short CAG repeats would be at higher risk of prostate cancer than men with relatively long CAG repeats and that African-American men would have shorter repeats on average than whites, who in turn would have shorter repeats than Asians.53
The hypothesis first received support from in vitro transfection assays demonstrating normal androgen binding but reduced AR-mediated transactivation activity, first in the abnormal range associated with Kennedy's disease54 and then in the normal range with transactivation being negatively correlated with CAG length.55 We and others have shown, as predicted, that African Americans have shorter CAG repeats on average than whites, who in turn have shorter repeats than Asians.53,56 Ingles and colleagues57 showed that, in whites, CAG length predicted prostate cancer risk, with risk increasing as length decreases. This effect was particularly pronounced for men presenting with advanced disease clinically. This finding, or a variant of it, has been the most reproducible to date in the molecular genetic epidemiology of prostate cancer. Studies done in diverse populations have rather consistently found that CAG repeat length is related either to prostate cancer risk overall, to advanced stage of prostate cancer if not prostate cancer risk overall, or age at onset of prostate cancer (see Table 16.1, Chapter 16).
Coetzee and colleagues have been attempting to better understand the mechanism behind the relationship of CAG repeat length and androgen transactivation efficiency. They have shown, e.g., that CAG modulation of transcription activity is dependent on the presence of coactivator proteins, particularly of the p160 family, which bind to the N-terminal domain of the AR, just downstream from the polyglutamine tract encoded by the CAG repeat.58,59
Work initiated on the CAG repeat and prostate cancer has led to additional research demonstrating the value of polygenic approaches to etiology. Xue and colleagues60 studied one of the "downstream" genes, i.e., a gene that is transactivated by the AR in conjunction with polymorphic variation in the AR CAG repeat. Initially, they demonstrated a correlation between PSA levels and CAG repeat length; the PSA gene is one of only a relatively few genes that are known to be controlled by the AR. The PSA gene contains a single-nucleotide polymorphism (SNP) in the ARE of its promoter re-gion.61 This polymorphic variant predicted risk of prostate cancer, especially advanced prostate cancer (RR = 2.0 and 2.4, respectively, for prostate cancer overall and for advanced disease)
in a population-based pilot case-control study.62 CAG repeat length alone predicted risk, but the greatest risk levels were observed for the CAG repeat size and the PSA variant in combination (RR = 4.6 overall and 9.6 for advanced disease). This work may demonstrate in principle the value of polygenic pathway-driven approaches to better understand prostate cancer etiology. This work may also connect two major potential etiological pathways in that the PSA gene encodes a protease that participates in cleavage of IGF-I from its main binding protein (see below, Insulin-like Growth Factor Signaling Pathways).63
Several other androgen-signaling genes have been preliminarily studied in the context of prostate cancer risk. Testosterone is synthesized from cholesterol in a series of enzymatic steps involving several of the cytochrome P-450 enzymes.64 The enzyme cytochrome P-450c17 catalyzes two sequential reactions of the biosynthesis of T, in both the gonads and the adrenals. The first step is the conversion of pregnenolone to 17-hydroxypregnenolone (hydroxylase activity), and the second is its subsequent conversion to C19 steroid dehydroepiandrosterone (lyase activity), a steroid with androgenic activity.64 The CYP17 gene on chromosome 10 encodes the P-450c17 enzyme involved in these two sequential reactions in T biosynthesis.65 A T-to-C transition SNP exists in the 5'-UTR of the CYP17 gene (A2 allele).66 While the functional relevance of this polymorphism is in dispute, it has been linked to polycystic ovarian cancer risk in women, male pattern baldness in men,66 various estrogen metabolic parameters,67 breast cancer risk factors,68 and breast cancer risk per se.68 One U.S. study found the CYP17 A2 allele to be associated with higher risk of prostate can-cer,69 whereas a Swedish study found the opposite.70 Obviously, additional epidemiological and basic research is needed to fully understand the role of this gene in prostate cancer development.
As discussed above, DHT is the most active intraprostatic androgen. It is synthesized from T by the enzyme steroid 5a-reductase and inactivated through a reductive reaction catalyzed by 3a- or 33-hydroxysteroid dehydrogenase. Thus, the dehydrogenase reactions initiate the irreversible inactivation of DHT in the prostate, and these enzymes are critical for the regulation of intraprostatic DHT steady-state levels by controlling its degradation rate. Activity of the two 3-hydroxysteroid dehydrogenase enzymes is significantly lower in abnormal compared to healthy prostatic tissue.71 Thus, DHT might accumulate because of slowed degradation. 33-Hydroxysteroid dehydrogenase activity in humans is encoded by two closely linked yet distinct loci: the HSD3B1 and HSD3B2 genes, both located on chromosome band 1p13.72 The type 1 gene (HSD3B1) encodes the isoform present in placenta and peripheral tissue such as skin and mammary gland, while expression of the type 2 enzyme is restricted to adrenals and reproductive organs.73 Thus, the type 2 enzyme encoded by the HSD3B2 gene would regulate DHT levels by initiating the inactivation of this potent androgen in the prostate. Cloning and characterization of the human HSD3B2 gene have revealed that it spans about 7.8 kb of genomic DNA in four exons (Fig. 15.3).74
The HSD3B2 gene may play dual competing roles in prostate cancer etiology: the enzyme product (noted above), is one of the two enzymes that irreversibly inactivates DHT in the prostate; however, it is also responsible for production of the adrenal androgen androstenedione, which can undergo further conversion to T.41 A complex dinucleotide repeat polymorphism exists in intron 3, for which multiple alleles have been described with substantial variation in frequency across race/ethnicity.75 In preliminary studies, several of these occur more frequently in prostate cancer patients than in healthy men.75 The number of candidate genes and their polymorphic variants in this pathway will continue to grow. The androgen-signaling pathway is highly intricate and complex, involving not just genes involved in androgen biosynthesis, transport, activation, and detoxification but also genes encoding coactivator proteins and a whole series of downstream genes, most of which have yet to be identified.
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