Oral Presentation 29th Lorne Cancer Conference 2017

Germline BRCA2 Mutations Drive Prostate Cancers with Increased Genomic Instability and Distinct Evolutionary Trajectories (#47)

Renea A Taylor 1 , Heather Thorne 2 , Mitchell G Lawrence 1 , Michael Fraser 3 , Julie Livingstone 4 , Shadrielle Melijah G Espiritu 4 , Ania Sliwinski 5 , Declan G Murphy 6 , Mark Frydenberg 1 , Damien Bolton 5 , David Clouston 7 , Paul C Boutros 8 , Robert G Bristow 8 , Gail P Risbridger 1
  1. Monash University, Clayton, VIC, Australia
  2. kConFab, Peter MacCallum Cancer Centre, Melbourne, Australia
  3. Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
  4. Ontario Institute for Cancer Research, Toronto, Canada
  5. Department of Urology, Austin Hospital, Melbourne
  6. Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
  7. TissuPath, Mt Waverly
  8. University of Toronto, Toronto, Canada

Germline mutation of BRCA2 substantially increases the lifetime risk of developing prostate cancer. In BRCA2-mutation carriers, localised prostate cancer fails treatment and rapidly progresses to metastatic castrate-resistant prostate cancer (mCRPC) with 5-year cancer specific survival rates of ~50-60%. The molecular origins of the clinical aggressiveness of BRCA2-mutant prostate cancer are unknown and understanding them may allow better treatment decision-making.

We profiled the genomes and methylomes of localised prostate cancer from 14 carriers of germline BRCA2 mutations using whole-genome sequencing, SNP array-based copy number analyses, and methylation arrays. We then compared the mutational profiles of BRCA2-mutant prostate cancer to a set of 200 sporadic prostate cancers. 

We showed that BRCA2-mutant prostate cancer has elevated genomic instability, measured by percent genome alteration, and elevated numbers and distinct patterns of single nucleotide variants and genomic rearrangements compared to sporadic tumours. BRCA2-mutant prostate cancer showed global hypomethylation relative to sporadic prostate cancer which was retained even after controlling for the increased copy number aberrations rate. Most importantly, we identified activation of pathways associated with aggressive disease, including the MED12/MED12L axis, which is frequently dysregulated in mCRPC, but not in localised cancer in men with sporadic disease.

Taken together, we show that localised BRCA2-mutant prostate cancers harbour increased genomic instability and a mutational profile that more closely resembles advanced disease, despite no exposure to androgen deprivation therapy. While the population frequency of BRCA2-mutation is relatively low, the aggressive natural history of these tumours may justify changes in clinical management such as upfront use of PARP inhibitors and combined chemotherapy and androgen deprivation therapy to block the rapid progression to mCRPC. Based on our provocative data, future clinical trials could also explore molecular inhibition of ATR, mTOR and GSK3A pathways in these patients.