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 (BRCA2ⁱ) 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 BRCA2ⁱ prostate tumors.