Comparison of Caucasian and African-American DNA repair alterations in men with metastatic prostate cancer.

Abstract

199 Background: Data on germline DNA repair defects and VUS rates are sparse in African American (AA) men with metastatic prostate cancer (PCa). Methods: Germline testing data from two centers with a significant percentage of metastatic AA PCa patients were combined and compared to Caucasian American (CA) with metastatic PCa. Fourteen canonical DNA repair genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51C, RAD51D) were assessed in all tested patients (pts) using a pathogenic/likely pathogenic (P/LP) classification. Variants of unknown significance (VUS) were assessed in an Invitae-derived dataset with consistent VUS reporting. Results: A total of 105 AA men with metastatic disease were evaluated and 7/105 of these men (6.67%) had P/LP alteration. Among the AA pt alterations, there were 4 pts with BRCA2, 2 pts with BRCA1, and 1 pt with PALB2. A total of 39/417 (9.3%) of CA metastatic patients had P/LP alterations in the canonical 14 genes. No differences were detected in the AA vs CA metastatic comparison (p=0.39). A total of 1/105 (0.95%) AA pts and 23/418 (5.5%) CA had non-BRCA P/LP mutations. The number of non-BRCA P/LP mutations were lower in the AA as compared to the CA men (p=0.045). When evaluating VUS calls in the metastatic AAs using Invitae multi-gene panels, 28/92 (30.43%) pts had a VUS in the canonical 14 genes as compared to 67/366 (18.31%) of the CA men. AAs were more likely than CA to have a VUS (p=0.010). These data indicate that metastatic AA pts and CA are not significantly distinct in the P/LP alterations in 14 canonical DNA repair genes but that there were lower percentages of P/LP in the AA non-BRCA gene subset. Further, when assessing these genes, it is clear that a VUS is more likely to be called in the AA men. Conclusions: Among men with metastatic PCa, AAs have similar rates of inherited P/LP alterations in 14 well accepted DNA repair genes as compared to CA men, however the non-BRCA gene P/LP alterations were less frequent among the AAs. Variants classified as a VUS were clearly higher in these AA pts as compared to the CA pts.