Pathology of Gastric Cancer for Precision Medicine

2018 Fiscal Year Final Research Report

• Project/Area Number: 26253021
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human pathology
• Research Institution: The University of Tokyo
• Principal Investigator: Fukayama Masashi 東京大学, 大学院医学系研究科(医学部), 教授 (70281293)
• Research Collaborator: USHIKU Tetsuo ; USHIKU Aya ; ABE Hiroyuki ; KUNITA Akiko
• Project Period (FY): 2014-06-27 – 2019-03-31
• Keywords: 胃癌 / 病理学 / 分子型 / 遺伝子異常 / 癌微小環境 / 癌幹細胞 / 多様性

Outline of Final Research Achievements

To promote precision medicine of gastric carcinoma (GC), we studied pathological characteristics of four molecular subtypes of GC (EBV-positive GC, microsatellite instable GC, chromosome instable GC, and genomically stable GC), which were recently proposed by the international genome research group (TCGA).
The mechanisms by which cancer cells escape from the host immune system have been clarified in EBV-positive GC (viral copy numbers, expression and gene amplification of PD-L1, regulation of dendritic cells via exosomes and maintenance of cancer stemness were studied) and in microsatellite instable GC (intramucosal multi-clonality and lost expression of HLA class I).
Chromosome instable GC and genomically stable GC respectively include potentially distinct subgroups. We identified and characterized the following subgroups, fetal gastrointestinal epithelium-like GC in the former, and RHOA-mutated GC and CLDN18-ARHGAP fusion gene-positive GC in the latter subtype of GC.

Free Research Field

人体病理学

Academic Significance and Societal Importance of the Research Achievements

胃癌の発生にはピロリ菌の慢性感染，慢性炎症が重要な役割を果たしているが，発生する胃癌は多様である．従来，組織像から腸型，びまん型に二大別して論じてきたが，胃癌個別化医療という観点からは不十分であった．本研究では分子機序に基づく病理学により，分子型の染色体不安定性胃癌の中に胎児消化管上皮類似癌，ゲノム安定性胃癌の中にRhoA遺伝子変異癌，融合遺伝子陽性癌というサブグループを同定し，特質を解明した．またEBV陽性胃癌，マイクロサテライト不安定性胃癌では免疫回避機構を明らかにした.
本研究により，分子型による胃癌病理学の有効性を示し，個別化医療の基盤となる胃癌病理学研究の方向性を定めることができた．