Nikolaos Giannareas

Prostate cancer (PCa) is the second most commonly diagnosed cancer type in men and among the most heritable forms of cancer with an estimated familiar risk of 57%. Genome-wide association studies (GWASs) have identified more than 280 single nucleotide polymorphism (SNP) loci associated with PCa risk and aggressiveness. However, the molecular and biological mechanisms, as well as the clinical impact of many PCa susceptibility loci remain to be investigated. In our study we found that PCa risk loci are greatly enriched for TF genes including HNF1B at 17q12. While aiming to unravel the oncogenic regulatory circuits of the 17q12/HNF1B locus, we observed strong expression quantitative trait loci (eQTL) signals for the plausible causative gene HNF1B with the SNPs involved in HNF1B regulation in PCa. HNF1B has been found to biologically direct pathways of genes associated with cell cycle progression and PCa severity. An unbiased genome-wide co-expression analysis reveals the most frequent somatic alteration TMPRSS2-ERG fusion in PCa as a transcriptional mediator of the 17q12 locus. We try to demonstrate an extensive germline-somatic interaction between TMPRSS2-ERG and the HNF1B locus which implies a genetic predisposition and progression of PCa. This is currently an excellent example of discovering the mechanistic action of the 17q12 multicancer locus and the role of HNF1B in other types of cancers.