Integrative genomic analysis of malignant mesothelioma to find therapeutic molecular targets

• Project/Area Number: 18K07212
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Hyogo Medical University
• Principal Investigator: Yoshikawa Yoshie 兵庫医科大学, 医学部, 講師 (10566673)
• Co-Investigator(Kenkyū-buntansha): 大村谷 昌樹 兵庫医科大学, 医学部, 教授 (60398229) ; 江見 充 兵庫医科大学, 医学部, 特別招聘教授 (90221118)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 悪性中皮腫 / ゲノム解析 / ゲノムコピー数変化 / ゲノム再構成

Outline of Final Research Achievements

In order to detect exon/gene level copy number alterations (CNAs) in malignant mesothelioma (MM), we developed the digitalMLPA that is a novel technique for CN detection which combines MLPA (multiplex ligation-dependent probe amplification) and NGS. digitalMLPA analysis of MMs found the characteristic chromothripsis-like pattern CNAs in MMs. Some patients with the epithelioid type MMs having a few one-allele deletion showed good prognosis, but others with the epithelioid type MMs having biallelic deletion of CDKN2A in the combined loss of BAP1, SETD2, TP53, and NF2 showed poor prognosis. In bi-phasic and sarcomatoid types MMs, the number of chromosomes with CNAs was large and CNAs of segmental gain and loss inner chromosome were detected. Copy number analysis using digitalMLPA would be useful to estimate patient’s prognosis.

Academic Significance and Societal Importance of the Research Achievements

悪性中皮腫は、化学療法抵抗性の極めて予後不良の腫瘍である。本学は本邦で最もMM患者数が多く、早期診断・治療に取り組んできたが、今なお診断後2年内に死亡する患者の方が多い。遺伝子解析によりchromothripsis-like patternが検出されず、CNA変化が少なければ予後は良好と予測される。当該患者の治療を軽減できる可能性が示され、QOL改善につながる。また予後不良患者腫瘍で共通してコピー数変化が生じる領域から、悪性化に寄与する遺伝子を見出し、本分子に対する分子標的薬の探索に研究を発展させることは治療法の開発につながり、基礎研究として意義深い。

Research Products

• [Int'l Joint Research] ハワイ大学がんセンター/ニュウ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/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/ニュウヨーク大学ランゴンメディカルセンター(米国)
• [Journal Article] Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma (2020)
  • Author(s): Bononi A, Goto K, Ak G, Yoshikawa Y, Emi M, Hassan R, Yang H, Carbone M.et al.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 117 Issue: 52 Pages: 33466-33473
  • DOI: 10.1073/pnas.2019652117
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epigenetic Alterations and Biomarkers for Immune Checkpoint Inhibitors-Current Standards and Future Perspectives in Malignant Pleural Mesothelioma Treatment. (2020)
  • Author(s): Yoshikawa Y, Kuribayashi K, Minami T, Ohmuraya M, Kijima T.
  • Journal Title: Front Oncol. Volume: 10 Pages: 554570-554570
  • DOI: 10.3389/fonc.2020.554570
  • Peer Reviewed / Open Access
• [Journal Article] Development of mesothelioma in situ and its progression to invasive disease observed in a patient with uncontrolled pleural effusions for 15 years (2020)
  • Author(s): Hidaka Kouko、Takeda Tetsushi、Kinoshita Yoshiaki、Nabeshima Kazuki、Tamiya Sadafumi、Yoshikawa Yoshie、Tsujimura Tohru
  • Journal Title: Pathology International Volume: 70 Issue: 12 Pages: 1009-1014
  • DOI: 10.1111/pin.13021
  • Peer Reviewed
• [Journal Article] Mesothelioma developing in carriers of inherited genetic mutations. (2020)
  • Author(s): Yoshikawa Y, Emi M, Nakano T, Gaudino G
  • Journal Title: Transl Lung Cancer Res. Volume: Feb. 9 Issue: S1 Pages: 67-76
  • DOI: 10.21037/tlcr.2019.11.15
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
• [Presentation] デジタルMLPAで検出される悪性中皮腫のゲノムコピー数変化 (2020)
  • Author(s): 吉川良恵、大村谷昌樹、玉置（橋本）知子、江見充
  • Organizer: 第79回日本癌学会総会
• [Presentation] Tumor suppressor BAP1 impairs the function of B cells－in vitro analysis using BAP1 knockout-B blastoid cells－ (2020)
  • Author(s): 木村美智、多田陽郎、木島貴志、大村谷昌樹、吉川良恵
  • Organizer: 第45回日本分子生物学会年会
• [Presentation] Genome editing using CRISPR/Cas9 to introduce the mutations detected in malignant mesothelioma patients into TSCE5 cells and functional assays (2020)
  • Author(s): 藤野真誠、木村美智、今坂舞、大村谷昌樹、吉川良恵
  • Organizer: 第45回日本分子生物学会年会
• [Presentation] Malignant mesothelioma patients with BAP1 and other germline mutations in relation to survival prognosis (2019)
  • Author(s): 吉川良恵、江見充、大村谷昌樹、玉置（橋本）知子
  • Organizer: 第78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] 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