The tumor mutational landscape of BRCA2-deficient primary and metastatic prostate cancer

Carriers of germlineBRCA2pathogenic sequence variants have elevated aggressive prostate cancer risk and are candidates for precision oncology treatments. We examined whetherBRCA2-deficient (BRCA2d) prostate tumors have distinct genomic alterations compared withBRCA2-intact (BRCA2i) tumors. Among 2536 primary and 899 metastatic prostate tumors from the ICGC, GENIE, and TCGA databases, we identified 138 primary and 85 metastaticBRCA2dtumors. Total tumor mutation burden (TMB) was higher among primaryBRCA2dtumors, although pathogenic TMB did not differ by tumorBRCA2status. Pathogenic and total single nucleotide variant (SNV) frequencies atKMT2Dwere higher inBRCA2dprimary tumors, as was the total SNV frequency atKMT2DinBRCA2dmetastatic tumors. Homozygous deletions atNEK3,RB1, andAPCwere enriched inBRCA2dprimary tumors, andRB1deletions in metastaticBRCA2dtumors as well.TMPRSS2-ETV1fusions were more common inBRCA2dtumors. These results identify somatic alterations that hallmark etiological and prognostic differences betweenBRCA2dandBRCA2iprostate tumors.