Analysis on genomic instability in malignant mesotheliomas of Japanese patients as therapeutic targets

• Project/Area Number: 15K08658
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Hyogo Medical University
• Principal Investigator: Tamaoki(Hashimoto) Tomoko 兵庫医科大学, 医学部, 名誉教授 (10172868)
• Co-Investigator(Kenkyū-buntansha): 吉川 良恵 兵庫医科大学, 医学部, 講師 (10566673) ; 中野 芳朗 兵庫医科大学, 医学部, 教授 (30360267) ; 小山 英則 兵庫医科大学, 医学部, 教授 (80301852) ; 大村谷 昌樹 兵庫医科大学, 医学部, 教授 (60398229)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 悪性中皮腫 / ゲノム不安定性 / マイクロサテライト不安定性（MSI) / BAP1遺伝子 / BAP1症候群 / 3p21領域 / 免疫チェックポイント阻害剤 / BAP１症候群 / ｐ５３欠損 / SETD2遺伝子 / MTAP遺伝子 / 腎細胞がん

Outline of Final Research Achievements

Somatic deletions and mutations in the BAP1 gene, located in 3p21, is one of the common characteristics of malignant mesotheliomas (MMs). Genomic analysis of the 3p21 region showed genomic instability with many microdeletions. Then, microsatellite instability (MSI) was tested, since MSI-high condition is a good marker of immune checkpoint inhibitors. But none of MM genomes showed MSI-high, suggesting that these inhibitors may not effective. Genomic instability was also detected in other chromosome regions. In several MMs, partial deletions of a gene was detected. Hence, replacement therapy of this gene may be effective for these MMs.
Recently, a few cases with BAP1 germline mutations (BAP1 syndrome) have been reported. These cases developed MMs with better prognosis than sporadic non-hereditary cases, suggesting that germline BAP1 mutations and BAP1-related genes may be new therapeutic targets.

Research Products

• [Int'l Joint Research] ハワイ大学/がんセンター/胸部腫瘍部門(米国)
• [Journal Article] High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma. (2016)
  • Author(s): Yoshikawa Y, Emi M, Hashimoto-Tamaoki T, Ohmuraya M, Sato A, Tsujimura T, Hasegawa S, Nakano T, Nasu M, Pastorino S, Szymiczek A, Bononi A, Tanji M, Pagano I, Gaudino G, Napolitano A, Goparaju C, Pass HI, Yang H, Carbone M.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 113 Issue: 47 Pages: 13432-13437
  • DOI: 10.1073/pnas.1612074113
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] デジタルMLPAとターゲットシーケンスによる癌の微小ゲノム欠損の検出 (2017)
  • Author(s): 吉川 良恵、大村谷 昌樹、玉置（橋本）知子、江見 充.
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] BAP1 mutations in malignant mesotheliomas: a comparison between Japanese and Caucasian patients. (2016)
  • Author(s): Yoshikawa Y, Emi M, Hashimoto-Tamaoki T
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜、横浜
  • Year and Date: 2016-10-06
• [Presentation] Chromosome 3p rearrangement and BAP1 mutations in renal cell carcinomas and malignant mesotheliomas． (2016)
  • Author(s): Hashimoto-Tamaoki T, Yoshikawa Y, Togo Y, Hirota S, Sato C, Yamamoto S
  • Organizer: The 13th International Congress of Human Genetics.
  • Place of Presentation: 京都国際会議場、京都
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] 日本人悪性中皮腫のゲノム解析. (2015)
  • Author(s): 玉置（橋本）知子, 吉川 良恵, 佐藤 智佳, 福岡 和也, 辻村 亨, 中野 孝司
  • Organizer: 日本人類遺伝学会 第60回大会
  • Place of Presentation: 京王プラザホテル（東京都）
  • Year and Date: 2015-10-15
• [Presentation] 悪性中皮腫と腎細胞がんで高頻度に検出されるBAP1及びPBRM1の変異比較 (2015)
  • Author(s): 吉川 良恵、江見 充、佐藤 鮎子、大搗 泰一郎、辻村 亨、中野 孝司、玉置（橋本） 知子
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-10-08