Discovery of a Recurrent Frameshift Ashkenazi Jewish Founder Mutation (F722fs) in the PARP Inhibitor-sensitive MMS22L Gene Associated with Higher Risk of Prostate Cancer.

Abstract

Background and objective: Most of the genes for which an association with susceptibility to prostate cancer (PCa) has been established (eg, BRCA2) are involved in DNA repair, with a subset involved in sensitivity to PARP inhibitor (PARPi) therapy. We systematically tested the association with PCa risk for 65 newly reported genes involved in these pathways.

Methods: Ancestry-specific association between loss-of-function (LoF) germline variants in these 65 genes and PCa risk was first tested between a cohort of PCa patients from Johns Hopkins University (Hopkins; n = 3,716) and population controls from the Genome Aggregation Database (gnomAD; n = 103,221). Results were confirmed in three additional PCa patient cohorts and the UK Biobank (UKB).

Key findings and limitations: Among men of Ashkenazi Jewish ancestry (ASJ), the carrier rate of LoF MMS22L mutations was significantly higher in the Hopkins PCa cohort than in the gnomAD control cohort. The association was confirmed in the UKB. Combined analysis of all cohorts revealed that the carrier rate for F722fs, an ASJ founder mutation, was 1.5% for PCa cases versus 0.31% for controls (odds ratio [OR] 4.9, 95% confidence interval [CI] 2.1-10.6; p = 1.44 × 10^-4, Fisher's test). The proportion of patients with aggressive disease was also significantly higher in the carrier group than in the noncarrier group (83% vs 27%; OR 12.3, 95% CI 2.2-132.5; p = 0.003, Firth test). Another founder mutation in the non-Finnish European population, c.340+1G>A, was significantly associated with PCa risk in the UKB (OR 7.7, 95% CI 2.6-21.0; p =5.10 × 10^-4, Firth test). Somatic DNA analysis and assessment of the response to PARPi therapy are needed.

Conclusions and clinical implications: Our results suggest that MMS22L is a novel major gene associated with PCa susceptibility. Its carrier rate and effect size are similar to those for BRCA2. If these results are validated, MMS22L could be used for stratification of PCa risk and aggressiveness.