Assessment of inherited DNA repair defects in African-American and Caucasian men with prostate cancer.

Abstract

185 Background: Pathogenic inherited DNA repair defects are well described in Caucasian American (CA) men with prostate cancer (PCa) but comparative data with large subsets of African-American (AA) men are limited. Methods: Herein we examine germline pathogenic/likely pathogenic defects (P/LP) in 14 well annotated genes involved in DNA repair pathways in a large Invitae Corporation (San Francisco) lab-derived dataset of men with PCa. Frequency of P/LP alteration were directly compared in AA men and CA men. Reliable data on metastatic rates, family history, and Gleason score are missing. These data are derived from “real-world” experiences using both academic and private practice sites in accordance with physician ordering practices. The number of men assessed for individual genes aberrations varied. The 14 genes were assessed in 148-213 AA men and 1760-2488 CA men. Results: Comparative data using Invitae assays have lower levels of P/LP DNA repair alterations (as a whole) in the assays from AA men as compared to CA men (7.5% vs 13.9%, P=0.008). The P/LP variants in AA men were BRCA2 (6/214, 2.8%), BRCA1 (3/213, 1.4%), PALB2 (2/182, 1.1%), ATM (2/206, 1.0%), RAD51C (1/148, 0.68%), CHEK2 (1/207, 0.48%), and PMS2 (1/212, 0.47%). No AA men in this data set had P/LP mutations in BARD1, BRIP1, MLH1, MSH2, MSH6, NBN, or RAD51D. Lower frequency of P/LP findings in non-BRCA alterations were notably different in AA men as compared to CA men (0.48% vs 3.11%, P=0.03). The frequency of BRCA P/LP variants was not distinct between the AA and CA men. Additional comparisons show that Invitae CA data set is similar to a well cited previously published metastatic PCa data set. Conclusions: Taken together these data from comparable commercial assays indicate that AA men with PCa in this large dataset have lower rates of germline DNA repair P/LP alterations as compared to CA men. These findings are driven by lower rates of P/LP alterations in the non-BRCA genes.