Shirota Hidekazu, Miyake Akimitsu, Kawamura Maako, Suzuki Shuhei, Saito Kensuke, Yasuda Jun, Shibata Hiroyuki, Saito Motonobu, Iwaya Takeshi, Tada Hiroshi, Shimada Muneaki, Kawamorita Naoki, Kanamori Masayuki, Miyauchi Eisaku, Niizuma Hidetaka, Iwasaki Tomoyuki, Kasahara Yuki, Imai Hiroo, Saijo Ken, Komine Keigo, Takahashi Masanobu, Niihori Tetsuya, Aoki Yoko, Furukawa Toru, Tamiya Gen, Ishioka Chikashi
Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan.
Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
Cancer Med. 2025 Apr;14(8):e70443. doi: 10.1002/cam4.70443.
Germline mutations in BRCA1/2 are known to cause hereditary tumors in the breast, ovary, and other organs. With the widespread adoption of comprehensive diagnostics, including comprehensive genomic profiling (CGP) tests for solid tumors, many patients with BRCA1/2 variants have been identified.
In this study, we extracted and analyzed cases of BRCA1/2 variants that were presumed to be germline, which were repeatedly detected using the CGP test for solid tumors in northeastern Japan. The frequencies of BRCA1/2 variants in regional areas were compared with those of healthy individuals or nationwide cancer cohorts to investigate regional distribution.
Our findings revealed regional disparities in BRCA1/2 pathogenic germline variants, while variants of unknown significance (VUS) showed no such differences. The regional distribution of BRCA1 and BRCA2 variants showed distinct patterns: pathogenic variants of BRCA1 exhibited regional differences and were less prevalent compared to VUS, whereas BRCA2 variants, including both pathogenic variants and VUS, did not exhibit such clear regional localization. This discrepancy in regional distribution between BRCA1 and BRCA2 variants could be attributed to factors such as the diversity of the genome, gender differences, and cancer types.
These results highlight the importance of considering regional differences in comparative cohort studies, particularly in assessing the differential extension of mutations in pathogenic changes and VUS. Moreover, a presumption of pathogenicity variants would need to be discussed at the regional level.
已知BRCA1/2基因的种系突变会导致乳腺、卵巢和其他器官的遗传性肿瘤。随着包括实体瘤综合基因组分析（CGP）检测在内的综合诊断方法的广泛应用，许多携带BRCA1/2变异的患者被识别出来。
在本研究中，我们提取并分析了日本东北部通过实体瘤CGP检测反复检测到的、推测为种系的BRCA1/2变异病例。将地区BRCA1/2变异的频率与健康个体或全国癌症队列的频率进行比较，以研究地区分布情况。
我们的研究结果揭示了BRCA1/2致病种系变异存在地区差异，而意义未明的变异（VUS）则没有这种差异。BRCA1和BRCA2变异的地区分布呈现出不同模式：BRCA1的致病变异存在地区差异，且与VUS相比更为少见，而BRCA2变异，包括致病变异和VUS，并未表现出如此明显的地区定位。BRCA1和BRCA2变异在地区分布上的这种差异可能归因于基因组多样性、性别差异和癌症类型等因素。
这些结果凸显了在比较队列研究中考虑地区差异的重要性，特别是在评估致病变化和VUS中突变的差异扩展时。此外，需要在地区层面讨论致病变异的推定。
