ESMO 2017: DNA repair gene panel mutations in young onset and aggressive v non-aggressive prostate cancer cases in the UK
For this study, the authors sequenced 175 genes in the DNA damage response and repair pathways among patients with prostate cancer diagnosed at < 65 years compared with controls in the UK (mean age of 76 years). Analysis for this study was from 1,346 prostate cancer cases and 1,186 controls. The authors identified 5,118 single nucleotide variants (SNVs) and 172 indels. Furthermore, 216 unique protein truncating variants were in 96 genes of the 175-gene panel. The total number of protein truncating variants in prostate cancer cases was significantly higher (n=181) than in controls (n=122), specifically in the BROCA gene set of 22 tumour suppressor genes (p = 0.002). Mutations in BRCA1, BRCA2, ATM, MSH5 and CHEK2 were three times more common in prostate cases compared with controls (p = 0.0018). To investigate if aggressive cases had a different mutation burden, Dr. Eeles and colleagues compared 204 aggressive (Gleason score>8) versus 1049 non-aggressive (Gleason score ≤7) cases. In the single variant analysis, one variant in BRCA2, rs28897754 (K2950N) showed association with a more aggressive phenotype (p = 0.0016). Gene burden testing showed BRCA2, MSH2, PALB2 and CHEK2 had an odds ratio > 3 in aggressive vs non-aggressive cases (14% vs 4% respectively). Finally, men who died of prostate cancer had a 17% incidence of mutations in a subset of the 175-gene panel.
The authors concluded that there is a higher percentage of DNA damage response and repair gene germline mutations in prostate cancer cases occurring among men < 65 years, and among those with aggressive and lethal disease. Based on these findings, the goal is to develop a testing panel for use in clinical care in the near future.
Speaker: Ros Eeles, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, United Kingdom
Co-Authors: E. Saunders (Sutton, United Kingdom) S. Wakerell (Sutton, United Kingdom) I. Whitmore (Sutton, United Kingdom) C. Cieza-Borrella (Sutton, United Kingdom) K. Govindasami (Sutton, United Kingdom) T. Dadaev (Sutton, United Kingdom) Z. Kote-Jarai (Sutton, United Kingdom) D. Leongamornlert (Cambridge, United Kingdom)
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain