Two-hit events occurred independently in bilateral breast cancer of a heterozygous double germline pathogenic variants carrier of BRCA1 and BRCA2

While patients with hereditary breast and ovarian cancer with both BRCA1 and BRCA2 germline pathogenic variants (PVs) are rare, carcinogenesis in these cases remains unclear. We examined two-hit events of heterochronous bilateral breast cancers in a patient with BRCA1 and 2 PVs. A 65-year-old woman developed right breast cancer (triple-negative type) at the age of 49 and left breast cancer (triple-negative type) at 55. Family history indicated that multiple relatives on her mother’s side also developed breast cancer. BRCA1/2 genetic testing (BRACAnalysis®) showed that she had variants in both the BRCA1 and BRCA2 ( BRCA1 :c.5193 + 2dup, BRCA2 :c.6952C > T/p.Arg2318*). According to the data from the test, the former was interpreted as likely pathogenic at Myriad Inc. Further examination regarding two-hit events in her bilateral breast cancers was obtained by somatic mutation analysis using DNA isolated from cut slide specimens of formalin-fixed and paraffin-embedded tumor samples. We first confirmed the pathogenicity of the BRCA2 variant by detecting unusual splicing of BRCA2 that entirely skipped exon 19 using cultured T cells of the proband. Loss of heterozygosity in BRCA1 was observed in her right breast cancer. On the other hand, a somatic nonsense PV in BRCA2 (variant allele frequency = 15%) was found in her left breast cancer. These data provide evidence of different carcinogenesis between left and right breast cancer. Clinical and pathogenic characteristics of patients harboring BRCA1 and BRCA2 germline PVs depend on the genes somatically mutated in wild alleles. Inactivation of BRCA1 or BRCA2 is associated with each breast cancer carcinogenesis.