Prostate Cancer

In Western Europe and the USA, PC is the most common cancer diagnosed in men and the second most common cause of death with a continuing increase in incidence.110 The evidence that PC has a genetic component is compelling from epidemiological and genetic studies; some high-risk genes have been identified, that when present may predispose a carrier to development of the disease.111 Examples of PC susceptibility genes include HPC1 on chromosome 1q24-25,112 HPCX on Xq27-28,113 BRCA1 on 17q21 and BRCA2 on 13q12,114 CAPB at 1p36,115 PCAP on 1q42.2-43116 and most recently ELAC2/HPC2 on chromosome 17p.117 The association between these high penetrance genes and PC susceptibility highlights the complex and multigenic mode of inheritance of PC, yet more common, lower penetrance susceptibility polymorphisms in genes may be implicated in a higher proportion of the sporadic PC disease burden and so have more relevance to public health.

The prostate was originally thought to be an immunologically privileged site. However, there is now good evidence that the prostate has a lymphatic system, can mount inflammatory immune responses and these responses—as evidenced by density of tumor infiltrating lymphocyes—may be associated with prognosis in PC (reviewed in ref. 118). The immune system may therefore play a role in the pathogenesis of PC, via regulation of tumor growth, while evasion of the immune response may play a role in disease progression. In addition, due to the critical role of angiogenesis in PC development,93 and based on our findings in CMM, we elected to determine whether polymorphisms in pro- and anti-inflammatory and pro-angiogenic cytokine genes were associated with susceptibility to and/or markers of prognosis in a case-control study of British Caucasian PC patients and population controls. Results indicated that the IL-10 -1082 AA 'low expression' genotype was significantly increased in incidence in the patient group (OR = 1.78), closely paralleling results in is again suggestive that genetically determined low levels of IL-10 production may be a risk factor in PC, via down-regulation of VEGF synthesis or enhanced lysis of tumor cells by NK cells. Again, results from this genetic study are in accordance with findings from IL-10 gene transfec-tion studies in this malignancy.39

Evidence for a role for polymorphism in pro-angiogenic genes was also provided by this study, which showed significant associations between genotypes associated with low VEGF and low IL-8 expression and protection from PC

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