Identification of genetic biomarkers for prostate cancer and colorectal cancer

Colorectal and prostate cancer are among the most prevalent malignant diseases and cause a tremendous socioeconomic burden. This thesis includes five interrelated studies in the field of molecular cancer epidemiology, all aiming to identify new genetic biomarker candidates for colorectal and prostate cancer. The unlimited proliferative potential of cancer cells is mostly mediated by reactivation of telomerase activity, a hallmark of cancer, and genetic variation in telomerase gene (TERT) is of crucial research interest. The influence of single nucleotide polymorphisms (SNPs) of TERT on colorectal cancer susceptibility was investigated in a case-control study of 3264 cancer cases, polyps and controls. In the same cohort, MNS16A, a polymorphic tandem repeat minisatellite of TERT, was examined. A new allele (VNTR-364) and a risk factor for colorectal cancer (VNTR-274) were discovered. MNS16A was also examined in 1165 prostate cancer cases and 674 benign prostate hyperplasia controls and a further novel variant allele (VNTR-212) was identified. Functional studies of MNS16A were performed in cell lines of colorectal, lung, and prostate cancer. The hypothesized relationship that shorter VNTRs were associated with higher promoter activity was confirmed and for the first time demonstrated in all six VNTRs. In a hypothesis-free approach, the first Austrian genome-wide association study of colorectal cancer and advanced adenomas investigated 580,000 SNPs in 6116 individuals. Both, single marker tests and a model selection approach were applied for interpretation of genome-wide SNP data. Several associations of new marker candidates with colorectal cancer and advanced adenoma risk were observed. All previously unreported marker candidates require evaluation in independent studies Das kolorektale Karzinom und das Prostatakarzinom zählen zu den häufigsten Krebserkrankungen und verursachen eine enorme sozioökonomische Belastung. Die vorliegende Dissertation umfasst fünf Studien aus dem Krebsforschungsgebiet „Molekulare ...