Semba Ryoko, Eguchi Hidetaka, Takatsu Mizuki, Hashizume Toko, Moteki Hideaki, Maeno Kazuma, Murakami Fumi, Watanabe Junichiro, Kutomi Goro, Arai Masami
Department of Breast Surgery, Juntendo University Nerima Hospital, Takanodai 3-1-10, Nerima-Ku, Tokyo, 177-8521, Japan.
Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Breast Cancer. 2025 Jul 2. doi: 10.1007/s12282-025-01740-4.
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.
虽然携带BRCA1和BRCA2种系双杂合性(GDH)的遗传性乳腺癌和卵巢癌患者很罕见,但这些病例中的致癌机制仍不清楚。我们研究了一名携带BRCA1和BRCA2 GDH的患者异时性双侧乳腺癌的双打击事件。一名65岁女性在49岁时患右乳腺癌(三阴性型),55岁时患左乳腺癌(三阴性型)。家族史表明,她母亲一方的多个亲属也患了乳腺癌。BRCA1/2基因检测(BRACAnalysis®)显示,她的BRCA1和BRCA2均有变异(BRCA1:c.5193 + 2dup,BRCA2:c.6952C > T/p.Arg2318Ter)。根据检测数据,前者在Myriad公司被解释为可能致病。通过使用从福尔马林固定石蜡包埋肿瘤样本的切片标本中分离的DNA进行体细胞突变分析,获得了关于她双侧乳腺癌双打击事件的进一步检查结果。我们首先通过使用先证者的培养T细胞检测到BRCA2完全跳过外显子19的异常剪接,从而证实了BRCA2变异的致病性。在她的右乳腺癌中观察到BRCA1杂合性缺失。另一方面,在她的左乳腺癌中还发现了BRCA2的体细胞无义致病变异(变异等位基因频率 = 15%)和APC的双打击事件(VAF = 80%)。这些数据提供了左右侧乳腺癌致癌机制不同的证据。携带BRCA1和BRCA2 GDH的癌症的临床和致病特征取决于野生等位基因中发生体细胞突变的基因。