Masami Arai

Two-hit events occurred independently in bilateral breast cancers in a germline double heterozygous carrier for BRCA1 and BRCA2

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.

Analysis of the conditions for applying BRCA genetic testing to women with breast cancer using the Japanese HBOC consortium and the Japanese organization of hereditary breast and ovarian cancer (JOHBOC) registry project database

Abstract Background Considering past research in Europe and the USA, the conditions for medical insurance coverage of BRCA1/2 genetic testing (GT) in Japan have been established as follows: 1. Breast cancer onset at 45 years or younger age; 2. Triple-negative breast cancer (TNBC) onset at 60 years or younger age; 3. Onset of two or more primary breast cancers; 4. Family history of breast cancer, ovarian cancer, or pancreatic cancer up to the third degree; 5. Male breast cancer, 6. Ovarian, fallopian, or peritoneal cancers. However, data to determine the importance and extent of each factor in the current conditions are insufficient. Consequently, this study aimed to assess the validity of insurance coverage conditions in Japan, elucidate the relationship between these conditions, and explore the possibility of proposing new indicators. Methods A total of 5987 breast cancer patients were enrolled from 92 centers participating in the HBOC consortium and the JOHBOC registry project. Of these, 5904 patients were analyzed after excluding 48 male breast cancer patients due to insufficient numbers for analysis and 35 patients whose age at breast cancer onset was unknown or unregistered. We compared 1,091 cases in which pathogenic variants (PVs) (BRCA1(B1s): 543, BRCA2(B2s): 548) were detected with 4580 cases in which no variants (non-Vs) were detected. Variants of uncertain significance (VUS: 233 cases) were not classified as either PVs or non-Vs for subsequent analysis. We investigated the validity of each condition under which an HBOC diagnosis could be considered for medical insurance coverage. Results Regardless of the insurance coverage conditions, the detection rate of pathogenic variants (DRPV) of all analyzed cases was 19.2%. The DRPV under the insurance coverage conditions for GT—‘Age of breast cancer onset ≤ 45 years,’ ‘TNBC onset at ≤ 60 years,’ ‘ ≥ 2 primary breast cancers,’ ‘Patients with breast cancer concurrent with ovarian cancer,’ and ‘ ≥ 1 family history of breast or ovarian cancer up to the third degree’—was 25.4%, 31.6%, 24.6%, 48.8%, and 25.6%, respectively. Those within the insurance coverage group showed a pathogenic variant detection rate of 21.1%, compared to only 5.6% outside of the coverage. Our analysis indicates that medical insurance coverage conditions effectively identify candidates for GT. Furthermore, when examining the number of conditions met and the positivity rate, the positivity rate was 11.2%, with only one condition met. This rate increases exponentially as more conditions are met, underscoring the importance of multiple matching conditions. Additionally, those with comorbid ovarian cancer or a family history of ovarian cancer are more likely to have a pathogenic variant. Additionally, we reevaluated cases who did not meet the medical insurance conditions. TNBC occurrence was significantly associated with B1s, even when restricted to onset age ≥ 61 years. Familial history of prostate cancer also significantly associated with B2s. Conclusion This study determined that the Japanese medical insurance coverage conditions effectively identified candidates eligible for GT. Consequently, it is imperative to disseminate information to all patients with breast cancer covered by insurance, emphasizing the opportunity for GT, particularly if they have ovarian cancer complications or a family history of ovarian cancer.

Differences in age at diagnosis of ovarian cancer for each BRCA mutation type in Japan: optimal timing to carry out risk-reducing salpingo-oophorectomy

We examined a correlation between age at diagnosis of OC and common mutation types in 3,517 probands that received The average age at diagnosis of OC in g There appears to be no difference in the age at diagnosis of OC depending on the type of