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

Carriers of germline BRCA2 pathogenic sequence variants have elevated aggressive prostate cancer risk and are candidates for precision oncology treatments. We examined whether BRCA2-deficient (BRCA2(d)) prostate tumors have distinct genomic alterations compared with BRCA2-intact (BRCA2(i)) tumors. Among 2536 primary and 899 metastatic prostate tumors from the ICGC, GENIE, and TCGA databases, we identified 138 primary and 85 metastatic BRCA2(d) tumors. Total tumor mutation burden (TMB) was higher among primary BRCA2(d) tumors, although pathogenic TMB did not differ by tumor BRCA2 status. Pathogenic and total single nucleotide variant (SNV) frequencies at KMT2D were higher in BRCA2(d) primary tumors, as was the total SNV frequency at KMT2D in BRCA2(d) metastatic tumors. Homozygous deletions at NEK3, RB1, and APC were enriched in BRCA2(d) primary tumors, and RB1 deletions in metastatic BRCA2(d) tumors as well. TMPRSS2-ETV1 fusions were more common in BRCA2(d) tumors. These results identify somatic alterations that hallmark etiological and prognostic differences between BRCA2(d) and BRCA2(i) prostate tumors.