MBD4 mutation caused by MSI and 5FU chemosensitivity in colorectal cancer

• Project/Area Number: 25860530
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: Iwaizumi Moriya 浜松医科大学, 医学部, 助教 (60444361)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: マイクロサテライト不安定性 / 大腸がん / 薬物療法 / 感受性 / 大腸癌 / MBD4 / 5FU / TAS102 / FTD

Outline of Final Research Achievements

We found biochemically that Truncated MBD4 (Tru MBD4) binds to 5FU incorporated into DNA with higher affinity than MBD4. TruMBD4 reduced the 5FU affinity of the MMR recognition complexes that determined 5FU sensitivity by previous reports, suggesting other mechanisms might be operative to trigger cytotoxicity. To analyze overall 5FU sensitivity with TruMBD4, we established Tru MBD4 overexpression in hMLH1-proficient or -deficient colorectal cancer cells followed by treatment with 5FU. 5FU-treated TruMBD4 cells demonstrated diminished growth characteristics compared to controls, independently of hMLH1 status. Flow cytometry revealed more 5FU-treated TruMBD4 cells in S phase than controls.

Research Products

• [Journal Article] A novel APC mosaicism in a patient with familial adenomatous polyposis. (2015)
  • Author(s): Moriya Iwaizumi, Ken Sugimoto, et al.
  • Journal Title: Hum Genome Var Volume: 10 Issue: 1 Pages: 15057-15057
  • DOI: 10.1038/hgv.2015.57
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Acidic tumor microenvironment downregulates hMLH1 but does not diminish 5-fluorouracil chemosensitivity. (2013)
  • Author(s): Iwaizumi M, Tseng-Rogenski S, Carethers JM
  • Journal Title: Mutat Res Volume: 747-748 Pages: 19-27
  • Peer Reviewed
• [Journal Article] 家族性胃癌 (2013)
  • Author(s): 椙村春彦、山田英孝、陶 弘、新村和也、岩泉守哉、嵩 眞佐子
  • Journal Title: 癌と化学療法 Volume: 40 Pages: 154-158
• [Presentation] Trifluridine to enhance cytotoxicity by DNA mismatch repair deficiency and subsequent MBD4 frameshift mutation in colorectal cancer. (2016)
  • Author(s): Satoshi Suzuki, Moriya Iwaizumi, Yasushi Hamaya, Kosuke Takagaki, Satoshi Osawa, Takahisa Furuta, Ken Sugimoto
  • Organizer: 2016 Gastrointestinal Cancers Symposium (ASCO-GI 2016)
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2016-01-21
  • Int'l Joint Research
• [Presentation] DNA mismatch repair deficiency induces resistance for 5FU but keeps sensitivity for FTD in colorectal cancer (2015)
  • Author(s): Satoshi Suzuki, Yasushi Hamaya, Moriya Iwaiziumi
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-10-08
• [Presentation] MBD4 frameshift mutation changes 5-fluorouracil (5FU) sensitivity in colorectal cancer.
  • Author(s): Iwaizumi M, Shinmura K, Ikuma M, Sugimura H
  • Organizer: The 7th Japan and US Collaboration Conference in Gastroenterology
  • Place of Presentation: 東京
• [Presentation] 腫瘍微小環境は大腸癌細胞のMLH1発現低下を誘導するが、5FUの耐性は誘導しない.
  • Author(s): 岩泉守哉、鈴木聡、椙村春彦、勝見章、大西一功
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] MBD4 frameshift mutation changes 5-fluorouracil (5FU) sensitivity in colorectal cancer.
  • Author(s): 岩泉守哉、大澤恵、山田貴教、杉本光繁、古田隆久、金岡繁
  • Organizer: 第11回日本臨床腫瘍学会学術集会
  • Place of Presentation: 仙台
• [Presentation] MBD4 Frameshift Mutation Enhances 5-Fluorouracil (5FU) Sensitivity in Colorectal Cancer.
  • Author(s): Iwaizumi M, Martin P, Tseng-Rogenski S, Kanaoka S, Carethers JM
  • Organizer: 2013 American Gastroenterological Association (AGA)/Digestive disease Week (DDW) annual meeting
  • Place of Presentation: Orlando, FL, USA