ASCO GU 2018: DNA Repair Gene Panel Mutations in Young Onset Prostate Cancer Cases in The United Kingdom

San Francisco, CA ( There is an increasing understanding and appreciation of the important role genetic predisposition plays in the development of prostate cancer (PCa), particularly in younger patients. While these are due both to common and rare germline variation, one particular focus has been in mutations in DNA damage response and repair pathways, such as BRCA-1 and BRCA-2.

Utilizing the strength of the NHS in the UK, the authors screened for 167 genes from DNA damage response and repair pathways within a UK-based cohort of men with early onset PCa (diagnosed at age < 65 years) and in control patients; they also assessed 8 PCa candidate genes (total 175 genes). They were able to test 1,285 PrCa cases and 1,163 controls.

5,086 single nucleotide variants (SNVs) and 175 insertion/deletions (indels) were identified. Of these, 233 unique protein truncating variants (PTVs) with mutant allele frequency (MAF) < 0.5% in controls were found in 97 genes of the screening panel.

The total proportion of PTV carriers in PCa cases was higher than in controls (14.5% vs. 11.6%, p=0.036; OR = 1.29, 95% CI 1.01-1.64). However, this difference seemed relatively small in the absolute scale.

They then use an adaptive combination of P values algorithm, ADA, to identify genes which best to distinguish PCa cases from controls. They applied this for genes with at least 2 carriers of PTVs. This analysis selected 20 genes (OR = 3.37, 95% CI 2.05-5.66, PADA= 5.99x10-3). Men with PTVs in these 20 genes were about 3.4-fold more likely to have PCa (5.8% vs. 1.8%).

They then subsequently compared men with aggressive PCa (Gleason score ≥ 8, n = 204) with non-aggressive PCa cases (Gleason score ≤ 7, n = 1049) and men with lethal PCa (cause of death PrCa, n = 183) with indolent cases (Gleason score ≤ 6, n = 563) to evaluate genes associated with poor clinical prognosis. Using ADA, 4 genes were selected for aggressive PCa (PADA= 0.006) and 2 of these also for lethal PCa (PADA= 0.057). The 4 genes were BRCA2, MSH2, ERCC2, and CHEK2_1100delC.

There were 3 genes that predisposed to PCa development and to aggressive PCa – BRCA2, CHEK2 (non 1100delC), and MSH2. ERCC2 was specific to aggressive PCa rather than PCa predisposition.

In terms of clinical outcomes of the men with PCa alone, there were 236 events for overall survival and 181 events for cause-specific survival. The 4-gene marker predicted much worse overall survival and cause-specific survival, especially when adjusting for Gleason score.

As such, the authors provide an 21 gene panel that they suggest may be useful for clinical testing. However, this needs to be assessed and validated in other datasets first. Their 4-gene risk panel specifically assesses for aggressive PCa.

Limitations / Discussion Points:
1. It is unclear why the comparator group to lethal PCa (cause of death = PCa) was men with Gleason 6 PCa. While it is true, men with Gleason 6 PCa are unlikely to die of PCa, they are not mutually exclusive.

Speaker: Ros Eeles

Co-Authors: Daniel Leongamornlert, Ed Saunders, Sarah Wakerell, Ian Whitmore, Tokhir Dadaev, Clara Cieza Borrella, Koveela Govindasami, Mark Brook, Artitaya Lophatananon, Kenneth Muir, David V Conti, Zsofia Kote-Jarai

Institution(s): Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom; Institute of Cancer Research, Sutton, United Kingdom; Institute of Cancer Research, London, United Kingdom; University of Manchester, Manchester, United Kingdom; Zilkha Neurogenetic Institute, USC Keck School of Medicine, Los

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA