Genetic Factors

Family History of Cancer

Prostate cancer etiology has a hereditary component. Numerous studies have consistently reported familial aggregation of prostate cancer, showing a two- to three-fold increased risk of prostate cancer among men who have a first-degree male relative (father, brother, son) with a history of prostate cancer.69 Recent data from a large twin study suggests that as much as 42% (95% CI 29-50%) of the risk of prostate cancer may be accounted for by genetic factors.70 Genetic factors involved in prostate cancer include individual and combined effects of rare, highly penetrant genes, more common weakly penetrant genes and genes acting in concert with each other.

High-Penetrance Markers

Segregation and linkage analyses have shown that certain early-onset prostate cancers may be inherited in an autosomal dominant fashion,71 and it is estimated that such hereditary prostate cancers (HPCs) due to highly penetrant genes may account for about 10% of all prostate cancer cases.70 Several family studies are currently underway to identify hereditary prostate cancer candidate genes. However, these investigations have proven to be difficult for several reasons.72 One is that, due to the high incidence of prostate cancer and the heterogeneity of tumors, it is possible that sporadic cases are included in HPC families, thereby reducing the statistical power to detect genes for HPC. In addition, because prostate cancer is generally diagnosed at a late age, it is often impossible to obtain DNA specimens from fathers of HPC cases, and sons of HPC cases are often too young to have developed prostate cancer. Therefore, studies of HPC families are often unable to include more than one generation. Finally, the genetic heterogeneity of prostate cancer makes it difficult to devise appropriate statistical transmission models that also account for multiple susceptibility genes, many of which may be at only moderate penetrance. Despite these challenges, seven loci have been described to date, including HPC1, ELAC2, HPCX, HPC20, CAPB, PCAP, and an unnamed locus at 8p22-23 (Table 2), and fine mapping has led to the identification of a number of candidate genes, including RNASEL, ELAC2 and MSR-1.73'74 The results of studies of these loci,75-95 which have been extensively reviewed elsewhere,73 have largely been mixed, with subsequent studies failing to replicate promising earlier findings. The absence of strong, consistent results for high penetrance markers strongly suggests that the heritable component of prostate cancer largely comprises effects of multiple factors, including common, weakly penetrant markers, possibly interacting with one another and with environmental factors.

Common Low-Penetrance Markers

Results of epidemiologic studies of common polymorphisms are summarized below and in Table 3 by biological pathway; several of these markers have been reviewed elsewhere.73'96-99 In reviewing these results, it is important to note that, as with any other epidemiologic exposure, replication of findings is critical to establishing causality. This is particularly true of genetic association studies, because the recent explosion of genetic data has increased the potential for publication bias as investigators and publishers become more selective about writing up and publishing findings.

Androgen Biosynthesis and Metabolism Pathway

Because prostate cancer is an androgen-dependent tumor, it is likely that markers in genes whose gene products are involved in androgen biosynthesis and metabolism (Fig. 3) may be associated with disease. Recent epidemiologic studies have investigated the role of polymorphisms of over 10 genes involved in androgen biosynthesis, metabolism, transport, and regulation. These data are promising and accumulating at a remarkable pace but still are too sparse to support a role for any particular gene.

Results for the androgen receptor (AR), which is involved in androgen binding and transport, are fairly consistent, showing that shorter CAG repeat lengths are associated with increased risk in most, but not all, pop-ulations.100-119 For the type II steroid 5a-reductase (SRD5A2), which converts testosterone to the more active androgen dihydrotestosterone, the results are mixed,110,119-133 with a recent meta-analysis showing modest

Fig. 3. Androgen biosynthesis and metabolism pathway.

risk increases associated with shorter TA repeats and the T allele of the A49T marker, but not for other studied markers.96 Markers in several other genes, including cytochrome p450-17 (CYP17), cytochrome p450-19 aromatase (CYP19), cytochrome p450-1A1 (CYP1A1) and cytochrome p450-3A4 (CYP3A4) have shown promising initial results that often cannot be replicated.110'111'119'120'125'134-148 Furthermore, recent initial studies of 17P-hydroxysteroid dehydrogenase 3 (HSD17B3) and 3 P-hydroxysteroid dehydrogenase 1 (HSD3B1) have shown promising results,149'150 but further study is needed to elucidate the role these may play in prostate cancer.

The totality of current data suggests that racial/ethnic variation exists in polymorphisms of genes involved in the androgen pathways.151'152 However, their role in prostate cancer needs to be clarified further.

Growth Factor and Non-Androgenic Hormone Pathways

Due to serological evidence linking them to prostate cancer, a number of studies have explored the prostate cancer risk associated with polymorphic markers in genes involved in the insulin and insulin-like growth factor (IGF) signaling pathway. However, while the only study of the insulin gene (INS)

has shown promising results, early studies of markers in the IGF-II and IGF binding protein-3 (IGFBP-3) genes have shown null results.94'119'153

Strong laboratory evidence showing chemoprotection of vitamin D against prostate cancer, in addition to suggestive but inconsistent sero-epidemiological studies' has led to numerous studies of the vitamin D receptor gene (VDR).100,119,154-166 However, despite promising early studies, a recent comprehensive meta-analysis showed no overall associations and concluded that markers in the VDR gene are unlikely to be major genetic determinants of prostate cancer risk.97

Carcinogen Metabolism Pathway

Genes encoding enzymes that metabolize carcinogens and other toxins may play a role in prostate cancer. However, results from several studies of markers in different glutathione-S-transferases (GSTs), including GSTT1, GSTP1 and GSTM1, have mostly been null.76'119'134'167-175 Recent initial epidemiologic studies of other genes in these pathways, including GSTM3 and N-acetyl transferase 2 (NAT2), have been positive but require confirmation.134'167

DNA Repair Pathway

The DNA repair pathway serves to prevent disruptions in DNA integrity that might otherwise lead to gene rearrangements, translocations, amplifications and deletions that may contribute to cancer development.176 Initial reports of markers in genes encoding DNA repair enzymes, including the X-ray repair cross-complementing group (XRCC1), human 8-oxoguanine glycosylase I (hOGG1) and the xeroderma pigmentosum group D (XPD), show promising results.177-180 These results, combined with strong biological plausibility, suggest that this may be a fruitful area for further research.

Chronic Inflammation Pathway

Several lines of evidence point to a role of inflammation in prostate cancer etiology, and studies of markers in the genes involved in inflammation are emerging.46 Initial studies show positive results for transforming growth factor-^ (TGF-fi) and COX-2181,182 and negative results for tumor necrosis factor-a-308 (TNF-a-308), interleukin-1p (IL-1fi) and peroxisome proliferator-activated receptor-y (PPAR-y).183,184 Evidence for a role of inflammation markers in prostate cancer is increasing. Given the biological plausibility of this hypothesis, this should be a fruitful area for future research.

Angiogenesis Pathways

The need for increased vasculature to support cancer growth is an area of research that is currently gaining momentum. Genetic investigations of angiogenesis in prostate cancer have thus far involved the vascular endothelial growth factor (VEGF) gene as well as the genes for IL-8 and IL-10, and the handful of studies conducted to date have shown positive results.142,183 These findings await further confirmation and support the notion that angiogenesis may indeed be involved in prostate cancer.

Biological Pathways Related to Dietary Factors

It is clear that genetic susceptibility to both Phase I and II enzymes (cytochrome p450) affects the association between certain dietary factors and prostate cancer risk. For example, the effect of cruciferous vegetables is related to both their high glycosinolate content and functional variations in enzymes, particularly GSTM1 and GSTT1, that metabolize glycosino-lates to isothiocyanates (ITCs).27 Thus, to better assess the role of ITCs in prostate cancer, studies with both comprehensive and reliable assessment of cruciferous vegetable intake and genetic polymorphisms in GSTM1 and GSTT1 will be required. Moreover, genetic polymorphisms in receptors and transcription factors that interact with these compounds may contribute to variations in response to cruciferous vegetable intake. With sufficiently large sample size and careful assessment of diet and genetic factors, this important area should be investigated further.

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