Integrative genomic analysis of malignant mesothelioma to find therapeutic molecular targets

2020 Fiscal Year Final Research Report

• 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
• Keywords: 悪性中皮腫 / ゲノム解析

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.

Free Research Field

遺伝子解析

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。