Detailed analysis of genome structural alteration on 3p21 and clinical application in environment-related cancers.

• Project/Area Number: 16K08982
• 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: EMI Mitsuru 兵庫医科大学, 医学部, 特別招聘教授 (90221118)
• Co-Investigator(Kenkyū-buntansha): 玉置 知子 (橋本知子) 兵庫医科大学, 医学部, 名誉教授 (10172868) ; 吉川 良恵 兵庫医科大学, 医学部, 講師 (10566673)
• Research Collaborator: YAMAMOTO shingo
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 悪性中皮腫 / 腎細胞がん / 環境癌 / ゲノム構造異常 / ゲノムコピー数変化 / ゲノムコピー数解析 / digitalMLPA / 環境がん / digital MLPA / 癌遺伝子診断 / ゲノムコピー数

Outline of Final Research Achievements

We have described that frequent somatic copy number loss throughout the 3p21 region harboring BAP1 and neighbor genes in malignant mesothelioma; many of these minute deletions were not contiguous but rather they alternated with exon segments showing oscillating copy number loss along the 3p21 region. We developed new diagnostic technique, digital MLPA for malignant mesothelioma, that can identify frequent minute biallelic deletions in tumor genome with high accuracy. This technique enabled us to identify frequent minute biallelic deletions in TP53 gene in malignant mesothelioma. In contrast, we found rather large monoallelic deletions encompassing whole short arm of chromosome 3 in renal carcinoma, thus, highlighting these minute oscillating copy number losses as unique features in malignant mesothelioma genome.

Academic Significance and Societal Importance of the Research Achievements

次世代シーケンサーによる塩基配列解析は盛んにされているが、ゲノムコピー数解析は市販のCGHアレイを用いたものが大半で、解像度は数十Kb単位である。我々は、エクソン単位のゲノムコピー数解析が精度高くできる網羅的解析手法を開発し、MMのゲノム変化の特徴を見出した。これまで変異の少ないと考えられてきたMMについて、新規手法を用い、新たなゲノム変化を捉えたことは学術的意義がある。digitalMLPAを用い、体液中のMMを検出する手法を開発できれば、いまだに余命が診断後1年未満であるMMの早期診断を可能にすることができ、社会的意義は大きい。

Research Products

• [Int'l Joint Research] ハワイ大学がんセンター/ニューヨーク大学ランゴンメディカルセンター(米国)
• [Int'l Joint Research] ハワイ大学/がんセンター(米国)
• [Journal Article] A Subset of Mesotheliomas With Improved Survival Occurring in Carriers of BAP1 and Other Germline Mutations (2018)
  • Author(s): Pastorino,S.,Yoshikawa,Y.,Pass,HI.,Emi,M.,Nasu,M.Pagano,I.Takinishi,Y.,Yamamoto,R.Minaai,M.,Hashimoto_Tamaoki,T.,Ohmuraya,M.,Goto,K.,Goparaju,C.,Sarin,KY.,Tanji,M.,Bononi,A.,Napolitano,A.,Gaudino,G.,Hesdorffer,M.,Yang,H.,Carbone,M.
  • Journal Title: J Clin Oncol Volume: 印刷中 Issue: 35 Pages: 3485-3494
  • DOI: 10.1200/jco.2018.79.0352
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Whole-exome sequencing and digital PCR identified a novel compound heterozygous mutation in the NPHP1 gene in a case of Joubert syndrome and related disorders (2017)
  • Author(s): Koyama S, Sato H, Wada M, Kawanami T, Emi M, Kato T
  • Journal Title: BMC Med Genet. Volume: 18 Issue: 1 Pages: 37-41
  • DOI: 10.1186/s12881-017-0399-2
  • Peer Reviewed / Open Access
• [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] Digital MLPA identifies large difference of frequency with homozygous deletion at CDK2A (p16) gene between in cultured cells and malignant mesothelioma tissues (2018)
  • Author(s): 江見充、吉川良恵、玉置（橋本）知子、大村谷昌樹
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Frequent detection of structural variations in TP53 gene of malignant mesothelioma by digital MLPA (2018)
  • Author(s): 吉川良恵、大村谷昌樹、玉置（橋本）知子、江見充
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Multiple minute homozygous deletions on 3p12 un malignant mesothelioma (2017)
  • Author(s): 江見充、吉川良恵、辻村亨、長谷川誠紀、中野孝司、Pass Harvey, Yang Haining, Carbone Michele
  • Organizer: 第76回日本癌学会総会
• [Presentation] Detection of multiple minute genomic deletions by digital MLPA and target NGS in tumors (2017)
  • Author(s): 吉川良恵、大村谷昌樹、玉置知子、江見充
  • Organizer: 第76回日本癌学会総会
• [Presentation] 悪性中皮腫での高頻度なホモ接合性欠失：環境がんでの観察 (2017)
  • Author(s): 江見 充，吉川 良恵，佐藤 秀則，大村谷 昌樹，Yang Haining, Carbone Michele
  • Organizer: 日本人類遺伝学会第62回大会
• [Presentation] 悪性中皮腫集積家系患者の生殖細胞系列ゲノムDNA解析 (2017)
  • Author(s): 吉川良恵、江見充、佐藤秀則、大村谷昌樹、Carbone Michele
  • Organizer: 日本人類遺伝学会第62回大会
• [Presentation] BAP1 がん症候群、分子遺伝学および家系学による患者の同定 (2016)
  • Author(s): 江見 充
  • 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、神奈川）
  • Year and Date: 2016-10-06
• [Presentation] 悪性中皮腫におけるBAP1遺伝子変異の日米比較 (2016)
  • Author(s): 吉川良恵、江見 充、玉置知子
  • 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、神奈川）
  • Year and Date: 2016-10-06
• [Presentation] Founder BAP1 Mutation in Four American Families Predisposes to Malignant Peritoneal Mesothelioma, Uveal Melanoma, and other cancers (2016)
  • Author(s): Mitsuru Emi, Haining Yang, Michele Carbon
  • Organizer: 13th International Congress of Human Genetics (ICHG 2016)
  • Place of Presentation: 京都国際会議場（京都）
  • Year and Date: 2016-04-04
  • Int'l Joint Research