Abstract
While patients with hereditary breast and ovarian cancer with germline double heterozygosity (GDH) for BRCA1 and BRCA2 are rare, carcinogenesis in these cases remains unclear. We examined two-hit events of heterochronous bilateral breast cancers in a patient with GDH for BRCA1 and BRCA2. 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.Arg2318Ter). 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 pathogenic variant in BRCA2 (variant allele frequency = 15%) and a two-hit event in APC (VAF = 80%) were also found in her left breast cancer. These data provide evidence of different carcinogenesis between left and right breast cancer. Clinical and pathogenic characteristics of cancers with GDH for BRCA1 and BRCA2 depend on the genes somatically mutated in wild alleles.