Common germline variants for prostate cancer risk: implication in DNA repair and TMPRSS2-ERG fusion formation
Genome wide association studies have identified an increasing number of common germline variants (CVs) that are moderately associated with prostate cancer (PrCa), but the underlying risk-mediating mechanisms remain elusive. The present study investigated the functional involvement of risk CVs in DNA repair, a pathway crucially involved in cancer predisposition, and their somatic subtype specificity in order to facilitate context specific candidate gene research. CVs were associated with DNA repair capacity in 128 healthy probands and with the presence of the somatic TMPRSS2-ERG (T2E) fusion in a meta-analysis involving 1221 PrCa cases. Striking loci were analyzed for candidate gene expression in histologically normal and tumor tissue pairs. The functional involvement of candidate genes in T2E fusion formation was further investigated by the T2E induction assay in a cell culture model. The most striking results were observed for rs10993994 on 10q11: PrCa risk allele carriers seemed to cope more efficiently with radiation-induced DNA double strand breaks (DSB) in a shorter time and were also more likely to develop T2E positive (T2E+) than T2E negative (T2E-) PrCa. The knockdown of the most intriguing candidate gene, PARG, resulted in a 3-fold increased T2E fusion induction in vitro. In addition, subtype-specific association analyses identified differentially associated variants on 17q24 with T2E+, and 8q24 with T2E- PrCa. In conclusion, categorizing of risk loci for mechanistic contexts has proven successful to diminish disease heterogeneity. The present study identified PARG as a novel PrCa candidate gene on the genomic region 10q11 that probably acts as a modulator of DSB repair and thus predisposes also for the T2E+ subtype. Two further loci, 8q24 and 17q24, were found differentially associated with the T2E fusion, highlighting the distinctness of T2E+ versus T2E- PrCa on the germline level.
Subject HeadingsMyc [GND]
DNA repair [MeSH]
Genom-wide association study [MeSH]
Polymorphism, single nucleotide [MeSH]
Prostatic neoplasms [MeSH]