Study on pathogenesis and cancer development in primary sclerosing cholangitis by genetic analysis of biliary epithelium

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K21543
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: Kyoto University
• Principal Investigator: Kakiuchi Nobuyuki 京都大学, 白眉センター, 特定准教授 (90839721)
• Project Period (FY): 2020-07-30 – 2022-03-31
• Keywords: 原発性硬化性胆管炎 / 胆管がん / 体細胞変異 / 陽性選択 / クローン拡大

Outline of Final Research Achievements

Epithelial organoids were prepared from bile and bile ducts of primary sclerosing cholangitis (PSC) patients and analyzed for somatic mutations in PSC and controls by whole genome sequencing. In addition, bile ducts from PSC liver transplant recipients were multi-sampled, and organoid cultures were used to purify the epithelium for whole exome analysis to assess the spread of mutant clones. We observed clones expanded across adjacent samples and clones with cancer driver mutations such as ARID2 and PIK3CA. This study allowed for in-depth analysis of epithelial clones and identification of genetic mutations that may be associated with PSC pathogenesis and carcinogenesis.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

本研究により、胆管オルガノイドをモデルとして、胆管上皮クローンの綿密な解析が可能であることが示された。発癌に関連する可能性のあるいくつかの遺伝子変異を同定するとともに、症例間の異種性から、複雑なPSCの病態が示唆された。本研究は、将来さらにPSC症例の解析を重ねることで、PSC病態や胆管発がんの解明に資すると考えられる。