BRCA2, ATM, and CDK12 Defects Differentially Shape Prostate Tumour Driver Genomics and Clinical Aggression
This week we profile a recent publication in Clinical Cancer Research from Evan Warner (pictured, left), Cameron Herberts (pictured, right), and Alex Wyatt at the Vancouver Prostate Centre.
Can you provide a brief overview of your lab’s current research focus?
The Wyatt laboratory at the Vancouver Prostate Centre has pioneered the use of circulating-tumor DNA (ctDNA) to characterize the genomic landscape of genitourinary cancers (e.g. prostate, bladder) and identify associations with patient clinical outcomes. This DNA can be extracted from plasma obtained via a simple blood draw (known as a “liquid biopsy”), eliminating the need for an invasive metastatic biopsy. This technology represents an inexpensive and minimally-invasive alternative to a standard tissue biopsy while still enabling researchers and clinicians to analyze tumor DNA. We hope that this will lead to better biomarkers for guiding therapy selection and enable a more personalized approach to patient treatment.
What is the significance of the findings in this publication?
Our team’s recent publication in Clinical Cancer Research focuses on late-stage prostate tumors harboring genetic defects that hinder the successful repair of DNA damage. Sequencing efforts have shown that disruption of DNA damage repair genes occur in >20% of advanced disease. While loss of DNA repair machinery is generally a poor prognostic factor (with these tumors exhibiting attenuated responses to many standard-of-care treatments), it can also create a therapeutic vulnerability to drugs that exploit a tumor’s inability to repair damaged DNA. Health Canada has recently approved the use of new treatments (poly ADP-ribose polymerase inhibitors) for prostate cancers with mutations in the BRCA or ATM genes, which are critically important to the DNA repair machinery. Mutations in BRCA genes can also create a heritable risk for development of several different cancers, including prostate, breast, and ovarian. Our recent publication highlights the use of liquid biopsy technology to accurately identify DNA repair defects in prostate cancer without the need for an invasive tissue biopsy. Moreover, we are able to provide insight into concurrent tumor mutations that accompany loss of DNA repair, and hypothesize how this might affect patient response to therapy. We hope that our findings will help identify those patients most likely to benefit from novel treatments targeting defective DNA repair, reducing futile use of expensive treatments with significant side-effects.
What are the next steps for this research?
Some prostate tumors have defective DNA damage repair, yet do not have a readily identifiable mutation in BRCA or ATM that explains their impaired repair capacity. Our future work will explore novel methodology to identify these tumors by looking at the genome-wide ‘scarring’ caused by defunct DNA repair machinery, enabling us to identify a greater proportion of patients who may benefit from targeted therapy. Over the past five years, the Wyatt laboratory at the Vancouver Prostate Centre has collaborated closely with Dr. Kim Chi (Medical Oncologist, Regional Medical Director at the BC Cancer Agency) to establish a province-wide ‘liquid’ biobank effort where serial plasma ctDNA is collected from metastatic cancer patients during disease treatment. As this biobank of samples continues to grow, we will further develop and improve clinical assays using ctDNA for the treatment of prostate cancer.
If you’d like us to mention your funding sources, please list them
This study was generously supported by a Canadian Institutes of Health Research (CIHR) project grant, the Prostate Cancer Foundation (USA), and Prostate Cancer Canada.