Mechanisms of carcinogenesis in individuals harboring germline BRCA1/2 pathogenic variants

• Project/Area Number: 18K16292
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Yamanashi Prefectural Hospital Organization
• Principal Investigator: Yosuke Hirotsu 地方独立行政法人山梨県立病院機構山梨県立中央病院(がんセンター局ゲノム解析センター), ゲノム解析センター, チーフ研究員 (10793838)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: BRCA1/2 / 生殖細胞系列 / 乳癌 / 卵巣癌 / PARP / 癌 / 遺伝性 / ゲノム / 変異

Outline of Final Research Achievements

Individuals with germline BRCA1/2 pathogenic mutations have a high-risk of the development of breast, ovarian, and prostate cancers. BRCA1/2 pathological variants are racially diverse. However, it remained systematically unknown the functional significance of BRCA1/2 variants and potential therapeutic targets to PARP inhibitors.
In this study, we examined the BRCA1/2 variants which were previously classified as benign, variants of uncertain significance (VUS) and pathogenic. We assessed these variants using database (MH-BRCA) and redefined some missense variants as likely pathogenic. Furthermore, we could assess whether tumor with these variants have a sensitivity to PARP inhibitor (i.e. olaparib).

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、VUSの再評価を行うことで、機能的に再分類されること、PARP阻害剤に対する感受性を再評価することの重要性があることを示した。
日本人で同定されるBRCA1/2バリアントに対し、データベースを使って解析をすることで、再評価が可能である考えられる。また、機能的意義が明らかになった癌に対して、ポリADP-リボースポリメラーゼ（PARP）阻害剤に対する感受性を評価することも可能である。

Research Products

• [Journal Article] Consolidated BRCA1/2 Variant Interpretation by MH BRCA Correlates With Predicted PARP Inhibitor Efficacy Association by MH Guide (2020)
  • Author(s): Hirotsu Y, Schmidt-Edelkraut U, Nakagomi H, Sakamoto I, Hartenfeller M, Narang R, Soldatos TG, Kaduthanam S, Wang X, Hettich S, Brock S, Jackson DB, Omata M
  • Journal Title: Int J Mol Sci Volume: 21 Issue: 11 Pages: 3895-3895
  • DOI: 10.3390/ijms21113895
  • Peer Reviewed / Open Access
• [Journal Article] Durable Response by Olaparib for a Japanese Patient With Primary Peritoneal Cancer With Multiple Brain Metastases: A Case Report (2019)
  • Author(s): Sakamoto I, Hirotsu Y, Nakagomi H, Ikegami A, Teramoto K, Omata M
  • Journal Title: J Obstet Gynaecol Res. Volume: 45 Issue: 3 Pages: 743-747
  • DOI: 10.1111/jog.13851
  • Peer Reviewed
• [Presentation] BRCA1/2生殖細胞系列変異保因者の癌組織中における遺伝子異常 (2019)
  • Author(s): 弘津 陽介
  • Organizer: 第27回日本乳癌学会
• [Presentation] Assessment of “hereditary risk of patients with bilateral breast cancer (2019)
  • Author(s): 中込 博
  • Organizer: 第17回臨床腫瘍学会
• [Presentation] BRCA variant classification is improved by Japanese SNP data and correlate with response to PARP inhibition in MH GUIDE (2019)
  • Author(s): Udo Schmidt-Edelkraut
  • Organizer: 第17回臨床腫瘍学会
• [Presentation] 遺伝性乳癌患者に対するリスク軽減乳房切除について (2019)
  • Author(s): 中込 博
  • Organizer: 第57回日本癌治療学会学術集会
• [Presentation] 遺伝子パネル検査の院内実装と精度管理・外部認定取得に向けて (2019)
  • Author(s): 弘津 陽介
  • Organizer: 第26回日本乳がん学会
• [Presentation] ゲノム情報と知識データベースの融合による治療薬の選択 (2019)
  • Author(s): 弘津 陽介
  • Organizer: 第22回分子標的治療学会
• [Presentation] Pathogenicity of BRCA Variants for Familial Breast and/or Ovarian Cancer (2019)
  • Author(s): 中込 博
  • Organizer: 第77回日本癌学会学術総会
• [Book] 臨床検体を用いたパネル検査 (2019)
  • Author(s): 弘津 陽介
  • Publisher: 肝胆膵 アークメディア
• [Remarks] 業績一覧
  • URL: https://www.ych.pref.yamanashi.jp/department02/509/