Molecular analysis of multiple sessile serrated lesions and establishment of surveillance system for high-risk patients with colorectal cancer

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07662
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Harada Taku 札幌医科大学, 医学部, 研究員 (60468030)
• Co-Investigator(Kenkyū-buntansha): 山本 英一郎 札幌医科大学, 医学部, 訪問研究員 (60567915)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 大腸鋸歯状病変 / 大腸がん / エピゲノム / ヒストン修飾 / DNAメチル化

Outline of Final Research Achievements

Patients with multiple serrated lesions are at high-risk of developing colorectal cancer. The aim of this study was to elucidate the mechanisms underlying the development of colorectal cancer from multiple serrated lesions and to establish surveillance for high-risk patients with colorectal cancer. Analysis of DNA methylation and histone modifications in serrated lesions and background mucosa revealed an elevated level of histone H3 lysine 27 trimethylation (H3K27me3), a marker of transcriptional repression, in the background mucosa of multiple serrated lesions. H3K27me3 in the background mucosa showed a positive correlation with DNA methylation in the tumor area, while H3K4me3 in the background mucosa showed a negative correlation with DNA methylation in the tumor area. Among these findings, TLX2 and GABRA4 were identified as candidate marker genes that frequently exhibit H3K27me3 in the background mucosa of multiple serrated lesions.

Free Research Field

消化器内科学

Academic Significance and Societal Importance of the Research Achievements

大腸腫瘍の背景粘膜においてDNAメチル化異常が蓄積するという報告はこれまでにも見られるが、本研究ではヒストン修飾が大腸腫瘍のfield defectに関わるという知見を得た。背景粘膜におけるヒストン修飾は、多発鋸歯状病変のリスクマーカーとして応用しうる可能性が示された。また、大腸粘膜におけるヒストン修飾が、大腸腫瘍発生におけるDNAメチル化異常のトリガーとなっている可能性を示した。