Abstract
Inadequate selenium intake is a risk factor for prostate cancer (PC). The cancer-protective effect of selenium is partly attributable to its incorporation into selenoproteins. Selenoprotein gene polymorphisms are associated with PC risk and epigenetic silencing of the selenoprotein glutathione peroxidase 3 (GPx3) by DNA methylation is common in PC. In this thesis, five SNPs, GPx1:Pro198Leu, GPx4:718C/T, selenoprotein-15:811C/T, selenoprotein-P (SEPPl):Ala134Thr, mitochondrial superoxide dismutase (SOD2):Va116Ala, were genotyped in the CAPS (Cancer of the Prostate in Sweden) study, a case-control study of 2915 PC cases and 1764 controls in a low selenium population. SOD2-Ala was associated with increased PC risk (OR 1. 19, 95%CI 1. 03-1. 37) vs SOD2-Val homozygotes. Interaction between SOD2 and SEPP1 polymorphisms was observed, with SEPP1-Ala234 homozygotes having higher risk of PC (OR 1. 43, 95%CI 1. 17-1. 76) and aggressive PC (OR 1. 60, 95%CI 1. 22-2. 09) if they were also SOD2-Alal6+ (interaction, PC P=0. 05, aggressive PC P=0. 01), an interaction that was even stronger for PC in ever-smokers (OR 1. 97, 95%CI 1. 33-2. 91; interaction P=0. 001). Genes methylated in PC were identified through re-expression of silenced genes after treatment of cell-lines with the demethylating agent 5-aza-2'-deoxycytidine, and by methylated DNA immunoprecipitation (MeDIP), followed by whole-genome micro-array analysis. GPx2 was methylated in PC cell-lines and tissues but not in normal prostate. The potential tumour suppressor genes ADAMTS12 and ID4 were shown to be hypermethylated in PC for the first time. RNF152 and LAYN were hypermethylated in the metastasis-derived PC cell lines, but not in primary tumour or normal tissue, implicating RNF152 and LAYN in metastatic disease. Pathway analysis identified several PC-relevant processes as both disrupted by DNA methylation and affected by selenium-supplementation, particularly pathways involving cell-adhesion. The evidence presented in this thesis further elucidates potential mechanisms by which selenium may exert a cancer protective effect and has identified several novel genes that may have potential as prognostic and/or diagnostic markers of PC.