Array CGH as a potential predictor of radiocurability in intermediate risk prostate cancer

Abstract

Prostate cancer is the most common male cancer and up to one fifth of diagnosed patients will die of their disease. Current prognostic variables including T-category (of the TNM staging), the absolute or kinetics of prostatic specific antigen (PSA) and the pathologic Gleason score (GS) are utilized to place men in low, intermediate and high-risk prostate cancer risk groupings. There is great heterogeneity within the non-indolent intermediate risk group with respect to clinical response. It is therefore imperative that further genetic and other prognostic factors be identified to better individualize treatment. Somatic alterations in prostate cancer. Herein, we review the potential for somatic alterations in tumor-associated genes (based on comparative genomic hybridization (CGH) in prostate cancers to be novel prognostic, and possibly predictive, factors for prostate cancer radiotherapy response. Intermediate risk prostate cancers show alterations in a number of genes thought to be involved in radiosensitivity, DNA repair, cell death and stem cell renewal. These include deletions at 21q (TMPRSS2: ERG), 13q (RB1), 10q (PTEN), 8p (NKX3.1), additions at 8q21 (containing c-Myc)) and haplo-insufficiency for p53, PARP1, ATM and DNA-PKcs. Conclusions. The use of high-resolution CGH for fine-mapping of deletions and amplifications in pre-radiotherapy prostate cancer biopsies is feasible. Genetic alterations may delineate localized prostate cancer from systemic disease and be used as a predictive factor in that patients would be individually triaged to local (surgery versus radiotherapy) and/or adjuvant (adjuvant androgen ablation or post-operative radiotherapy) therapies in a prospective fashion to improve outcome. The knowledge of abnormal DNA repair pathways within in a given patient could allow for the judicious use of targeted agents (PARP/ATM inhibitors) as personalized medicine.

Acknowledgments

We thank Charles Catton, Michael Milosevic, Brad Wouters, Chad Malloff, Theo van der Kvast, Jeremy Squire, and Wan Lam for helpful discussions. Supported by operating grants from Prostate Cancer Canada, the Terry Fox Research Institute, the Ontario Institute for Cancer Research, the US Army DOD Prostate Program and an infrastructure grant from the Canadian Foundation for Innovation grant to the STTARR Innovation Facility. This research was also funded in part by the Ontario Ministry of Health and Long Term Care. The views expressed do not necessarily reflect those of the OMOHLTC. RGB is a Canadian Cancer Society Research Scientist. AI holds a Canadian Urology Oncology Group Post-Doctoral Award and JT is a CFCRI–OCI Prostate Cancer Fellow.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.