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.