Comprehensive genetic analysis of the colorectal serrated neoplasia pathway

• Project/Area Number: 18K15796
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Juntendo University
• Principal Investigator: Murakami Takashi 順天堂大学, 医学部, 准教授 (10568158)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: serrated pathway / 大腸鋸歯状病変 / 大腸癌発育進展 / serrated lesion / sessile serrated lesion / SSA/P / NBI併用内視鏡 / MSI / BRAF / 鋸歯状ポリポーシス症候群 / 鋸歯状腺癌 / SSAP / MLH1 / 次世代シーケンシング（NGS） / FBXW7 / TP53 / 大腸癌 / 網羅的遺伝子解析

Outline of Final Research Achievements

Lost MLH1 expression was found in 5 cases. All lesions studied were positive for nuclear β-catenin expression. Regarding phenotypic mucin expression, all lesions were positive for MUC2, but negative for CD10. MUC5AC and MUC6 positivity was observed in 7 cases. Genetically, the most frequently mutated gene was BRAF (7 cases), and other mutations were detected in FBXW7 (3 cases); TP53 (2 cases), and KIT, PTEN, SMAD4, and SMARCB1 (1 case each). Furthermore, 4 of 8 lesions were MSI-high and the remaining 4 lesions were microsatellite-stable (MSS). Interestingly, all 4 MSI-high lesions displayed MLH1 loss, 3 of which harbored a FBXW7 mutation, but not a TP53 mutation. However, 2 MSS lesions harbored a TP53 mutation, although none harbored a FBXW7 mutation.

Academic Significance and Societal Importance of the Research Achievements

serrated neoplasia pathwayはその発育進展にBRAF変異、Wnt/β-cateninシグナルの活性化、胃腸混合型粘液形質が関与すると考えられた。さらにserrated neoplasia pathwayはMSI大腸癌へと進展する経路のみならずMSS大腸癌へと進展する2つの経路が存在し、前者ではMLH1発現低下やFBXW7変異、後者ではTP53変異が関与するなど異なる分子生物学的特徴を有する可能性が示唆された。BRAF変異MSS大腸癌は組織学的に悪性度の高い病変として知られており、serrated neoplasia pathwayのさらなる解析が望まれる。

Research Products

• [Journal Article] Sessile serrated lesions: Clinicopathological characteristics, endoscopic diagnosis, and management (2022)
  • Author(s): Murakami T, Kurosawa T, Fukushima H, Shibuya T, Yao T, Nagahara A.
  • Journal Title: Digestive endoscopy Volume: - Issue: 6 Pages: 1096-1109
  • DOI: 10.1111/den.14273
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 鋸歯状病変由来を疑わせる進行癌はどのような病変か？ (2022)
  • Author(s): 村上 敬，八尾 隆史，黒澤 太郎，永原 章仁
  • Journal Title: 消化器内視鏡 Volume: 34
  • Peer Reviewed
• [Presentation] Dysplasiaまたは早期癌併存SSA/PのNBI併用内視鏡の有用性に関する検討 (2021)
  • Author(s): 村上 敬，八尾 隆史，永原 章仁
  • Organizer: 第101回日本消化器内視鏡学会総会
• [Presentation] 免疫組織化学、次世代シーケンシング、MSI解析に基づくSSA/P併存早期大腸癌の分子生物学的特徴 (2020)
  • Author(s): 村上 敬、赤澤 陽一、谷田貝 昂、田島 譲、立之 英明、齋藤 剛、坂本 直人、八尾 隆史、永原 章仁
  • Organizer: 日本消化器内視鏡学会総会
• [Presentation] 免疫組織化学、次世代シーケンシング、MSI解析に基づくSSA/P併存早期大腸癌の分子生物学的特徴 (2019)
  • Author(s): 村上 敬、赤澤 陽一、谷田貝 昂、田島 譲、立之 英明、齋藤 剛、坂本 直人、八尾 隆史、永原 章仁
  • Organizer: 第97回日本消化器内視鏡学会総会
• [Presentation] Molecular biological characteristics of colorectal sessile serrated adenoma/polyp with dysplasia or invasive carcinoma (2018)
  • Author(s): Takashi Murakami, Yoichi Akazawa, Tsuyoshi Saito, Tomoyoshi Shibuya, Naoto Sakamoto, Akihito Nagahara, Takashi Yao
  • Organizer: Digestive Disease Week 2018
  • Int'l Joint Research