Epigenetic Analysis of the Kallikrein Gene Family and Associated Pathways as a Novel Panel of Prostate Cancer Biomarkers
Year: 2015
Type: dissertation
Study design: Observational Study
Abstract: Aberrant epigenetic landscape is a hallmark of prostate cancer (PCa), one of the most common cancers among men worldwide. Currently, improved understanding of the molecular mechanisms driving PCa pathogenesis as well as biomarkers for improved diagnosis, prognosis and treatment of the disease are needed. Kallikrein related peptidases (KLKs) have emerged as important cancer biomarkers. However, the mechanisms leading to their deregulation in PCa are poorly understood. This thesis characterized the clinical impact of epigenetic mechanisms that regulate KLKs and associated genes contributing to PCa pathogenesis. Utilizing genome-wide DNA methylation profiling and quantitative MethyLight technology, novel tumor-specific hypermethylation of KLK6 and KLK10 was identified in PCa. KLK10 DNA methylation was associated with pathological stage and longer time to biochemical recurrence in two independent cohorts of PCa patients. KLK6 hypermethylation was observed in normal-appearing prostate tissue adjacent to PCa, which could be indicative of the epigenetic field effect. Through the use of qPCR microRNA arrays a signature of 42 upregulated microRNAs predicted to target KLKs was identified in association with Gleason score (GS)8 vs. GS6, but no signature was found in correlation with biochemical recurrence. Among these, the association of increased miR-137 with increasing GS was established in an independent cohort. Notably, expression of miR-137, predicted to target KLK10, was inversely correlated to KLK10 hypermethylation. The emerging independent clinical significance of clinicopathologic entities such as intraductal carcinoma (IDC) and carcinoma with cribriform architecture in PCa prognosis was further explored by investigating DNA hypermethylation alterations of selected candidate genes including KLK10 in association with these clinicopathologic entities. Although KLK10 methylation did not correlate with either IDC or cribriform architecture, the previously discovered methylation of APC, RASSF1A and TBX15 was significantly linked to these features in PCa. Further, the presence of large cribriform architecture or HOXD3 hypermethylation was a strong independent predictor of biochemical recurrence. Thus, this thesis presents a panel of methylated genes that demonstrated promising prognostic performance and investigated their role in the etiology of PCa. Accordingly, a novel multiplex MethyLight assay was developed for simultaneous analysis of three methylated genes with potential applications in research and clinical settings.
Source: TSpace (University of Toronto)
Author: Ekaterina Olkhov‐Mitsel
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2564179036