2020 Fiscal Year Final Research Report

Elucidation of the mechanism of hereditary breast cancer caused by a novel germline mutation in BRCA2

Research Project

PDF

Project/Area Number	18K08557
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 55010:General surgery and pediatric surgery-related
Research Institution	Chiba Cancer Center (Research Institute)
Principal Investigator	NAKAMURA RIKIYA 千葉県がんセンター(研究所), その他部局等, その他 (50456026)
Co-Investigator(Kenkyū-buntansha)	横井左奈千葉県がんセンター(研究所), 遺伝子診断部, 部長 (30372452) 山本尚人千葉県がんセンター(研究所), 乳腺外科, 部長 (40506169) 末永雄介千葉県がんセンター(研究所), 発がん研究グループ発がん制御研究部, 研究員 (80581793)
Project Period (FY)	2018-04-01 – 2021-03-31
Keywords	遺伝性乳癌
Outline of Final Research Achievements	Pathogenic variants in the tumor suppressor gene BRCA2 increase the incidence of breast and ovarian cancer and cause hereditary breast and ovarian cancer syndrome (HBOC). Recently, we discovered a novel BRCA2 missense variant of uncertain significance in a patient with a family history of breast cancer. The variant was inherited within the family, and the sister and father carrying the variant developed breast and pancreatic cancer, respectively. The location of the variant is on a oligonucleotide binding domain of BRCA2 that is essential for DNA binding. In this study, we biochemically verified the reduction of the homologous recombination activity for DNA double strand break. We also used genome editing to generate knock-in mice with the novel variant. As a result, reproductive organ abnormalities and ovarian tumor were observed in one strain.
Free Research Field	Breast Surgery
Academic Significance and Societal Importance of the Research Achievements	生まれながらにBRCA2の病的変異を有することは遺伝性乳癌卵巣癌症候群の確定診断となり、体質に合った抗がん剤の選択や、将来の癌リスクに対して早期からの精密検診、高リスク臓器の予防的切除といった対処法を選択できる。本研究により、これまで病的意義が不明であったBRCA2ミスセンス変異が病的であるとわかると、本人のみならず、きょうだいやこどもが同じ体質を共有するか診断でき、癌治療の選択肢を増やしたり、将来の癌リスクに対する予防が可能になるため、癌の生存率の改善に寄与し、医療経済にも貢献すると期待される。