Diagnostic and Prognostic Biomarkers for Early Prostate Cancer
Prostate cancer diagnosis and prognosis , Biomarker discovery and validation , DNA methylation , Cancer epigenetics , Tumor suppressors , PTEN Immunohistochemistry
Prostate cancer is diagnosed and treated primarily on the basis of histopathological assessment of biopsies and cancer extent. Unfortunately, this assessment, performed by pathologists on very small amounts of biopsy tissue, misrepresents patient’s true risk of having life-threatening cancer grade by as much as 50%. Hence there is an urgent need for robust diagnostic and prognostic biomarkers that can accurately identify patients with prostate cancer and stratify them according to the risk of developing aggressive disease state. We addressed this issue by focusing on DNA methylation, and PTEN and ERG protein markers in a large biomarker study. During this study we overcame several technical challenges associated with a typical biomarker discovery/validation approach such as cohort development and sample collection, and recovery of high-quality nucleic acids from archival tissues for proper testing of selected molecular features in downstream analysis. There is emerging evidence supporting a role of DNA methylation in initiation and progression of prostate cancer. We assessed DNA methylation levels at 15 loci using methylation-specific PCR and measured differences in their abundance levels in benign and cancer tissue samples. Several DNA methylation alterations were found to be highly cancer-specific, and a subset of them were significantly associated with prostate cancer grade group and biochemical recurrence. Loss of the PTEN tumor suppressor is a powerful prognostic biomarker in prostate cancer. However, the significance of tumour heterogeneity and partial PTEN loss are not clearly defined, nor are interactions between PTEN loss and the TMPRSS2-ERG fusions, the most common genetic aberration found in prostate cancer. We investigated their prognostic utility using immunohistochemistry. PTEN loss, but not ERG fusion, was significantly associated with biochemical recurrence. In addition, quantitative assessment of PTEN protein loss showed more prognostic relevance than conventional binary assessment. By conducting thorough assessment of DNA methylation alterations, and genetic mutations involving PTEN and ERG, we provide necessary evidence needed to demonstrate the prognostic utility of these markers.