Analysis of microbiome and epigenetics for the development of novel biomarker in Gastrointestinal cancers

• Project/Area Number: 17KK0195
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: General surgery
• Research Institution: Kumamoto University
• Principal Investigator: BABA Yoshifumi 熊本大学, 病院, 特任准教授 (20599708)
• Project Period (FY): 2018 – 2020
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥15,600,000 (Direct Cost: ¥12,000,000、Indirect Cost: ¥3,600,000)
• Keywords: 腸内細菌 / 食道癌 / エピジェネティクス / LINE-1 / Fusobacterium nucleatum / Microbiome / Fusobacterium / 大腸癌 / microbiome / epigenetics / gastrointestinal cancer

Outline of Final Research Achievements

We previously demonstrated the relationship of human microbiome Fusobacterium nucleatum with unfavorable clinical outcomes and inferior chemotherapeutic responses in esophageal cancer. Global DNA methylation is associated with the occurrence and development of various cancers. In our previous study, LINE-1 hypomethylation (i.e., global DNA hypomethylation) was associated with a poor prognosis in esophageal cancer. As the gut microbiota may play crucial roles in the DNA methylation of host cells, we hypothesized that F. nucleatum might influence LINE-1 methylation levels in esophageal cancer.F. nucleatum DNA was related to the LINE-1 hypomethylation of tumor lesions in esophageal cancer (P < 0.0001). We found that the impact of F. nucleatum on clinical outcomes was not modified by LINE-1 hypomethylation (for interaction P = 0.014).

Academic Significance and Societal Importance of the Research Achievements

腸内細菌叢はプロバイオティクス（Probiotics；人体に有益な腸内細菌叢ならびにこれらを含む食品・製品）やプレバイオティクス（Prebiotics；腸内細菌叢のバランスを改善する作用がある物質）により後天的に変化させることができる。今後の研究において、食道扁平上皮癌におけるFusobacteriumとエピジェネティクスの関係がより詳細に解明されれば、がん治療の新たな創薬に繋がる可能性があると考えている。

Research Products

• [Int'l Joint Research] Dana-Farber Cancer Institute（Harvard university）(アメリカ) (2019)
• [Journal Article] The Prognostic Role of Macrophage Polarization in the Colorectal Cancer Microenvironment (2020)
  • Author(s): Vayrynen JP, Baba Y, et al.
  • Journal Title: Cancer Immunology Research Volume: 9 Issue: 1 Pages: 8-19
  • DOI: 10.1158/2326-6066.cir-20-0527
  • Peer Reviewed
• [Journal Article] Prognostic Significance of Immune Cell Populations Identified by Machine Learning in Colorectal Cancer Using Routine Hematoxylin and Eosin?Stained Sections (2020)
  • Author(s): Vayrynen JP, Baba Y, et al.
  • Journal Title: Clinical Cancer Research Volume: 26 Issue: 16 Pages: 4326-4338
  • DOI: 10.1158/1078-0432.ccr-20-0071
  • Peer Reviewed
• [Journal Article] Metabolic Profiling of Formalin-Fixed Paraffin-Embedded Tissues Discriminates Normal Colon from Colorectal Cancer (2020)
  • Author(s): Arima K, Lau MC, Zhao M, Haruki K, Kosumi K, Mima K, Gu M, V&auml;yrynen JP, Twombly TS, Baba Y, Fujiyoshi K, Kishikawa J, Guo C, Baba H, Richards WG, Chan AT, Nishihara R, Meyerhardt JA, Nowak JA, Giannakis M, Fuchs CS, Ogino S
  • Journal Title: Molecular Cancer Research Volume: - Issue: 6 Pages: 883-890
  • DOI: 10.1158/1541-7786.mcr-19-1091
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Association of autophagy status with amount of Fusobacterium nucleatum in colorectal cancer (2020)
  • Author(s): Haruki K, Kosumi K, Hamada T, Twombly TS, V&auml;yrynen JP, et al.
  • Journal Title: The Journal of Pathology Volume: 250 Issue: 4 Pages: 397-408
  • DOI: 10.1002/path.5381
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] IDO1 Expression Is Associated With Immune Tolerance and Poor Prognosis in Patients With Surgically Resected Esophageal Cancer. (2018)
  • Author(s): Kiyozumi Y, Baba Y, Okadome K, Yagi T, Ishimoto T, Iwatsuki M, Miyamoto Y, Yoshida N, Watanabe M, Komohara Y, Baba H.
  • Journal Title: Ann Surg Volume: Mar 27 Issue: 6 Pages: 1-1
  • DOI: 10.1097/sla.0000000000002754
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic Nutritional Index, Tumor-infiltrating Lymphocytes, and Prognosis in Patients with Esophageal Cancer (2018)
  • Author(s): Okadome Kazuo、Baba Yoshifumi、Yagi Taisuke、Kiyozumi Yuki、Ishimoto Takatsugu、Iwatsuki Masaaki、Miyamoto Yuji、Yoshida Naoya、Watanabe Masayuki、Baba Hideo
  • Journal Title: Annals of Surgery Volume: 271 Issue: 4 Pages: 1-1
  • DOI: 10.1097/sla.0000000000002985
  • Peer Reviewed
• [Presentation] バイオマーカー開発を目指した食道癌における腫瘍免疫及び免疫チェックポイントの網羅的検討 (2020)
  • Author(s): 馬場祥史
  • Organizer: 第75回日本消化器外科学会総会
• [Presentation] 食道癌における腫瘍免疫の網羅的解析；免疫関連バイオマーカー開発を目指して (2020)
  • Author(s): 馬場祥史
  • Organizer: 第120回日本外科学会定期学術集会
• [Presentation] 食道癌コホートを用いたFusobacterium nucleatumと腫瘍免疫の統合解析 (2019)
  • Author(s): 小澄敬祐、馬場祥史、山村謙介、岡留一雄、八木泰佑、清住雄希、岩槻政晃、長井洋平、吉田直矢、馬場秀夫
  • Organizer: 第74回日本消化器外科学会総会
• [Presentation] Fusobacterium nucleatumの食道癌進展への関与とそのメカニズム；腫瘍免疫、NF-kB経路との関連 (2019)
  • Author(s): 野元大地、馬場祥史、秋山貴彦、岡留一雄、山下晃平、坂本悠樹、大徳暢哉、織田枝里、内原智幸、徳永竜馬、原田和人、山村謙介、江藤弘二郎、日吉幸晴、長井洋平、岩槻政晃、石本崇胤、岩上志朗、宮本裕士、吉田直矢、馬場秀夫
  • Organizer: 第30回日本消化器癌発生学会総会
• [Presentation] LINE-1 methylation level and local immune response in esophageal cancer (2018)
  • Author(s): Yoshifumi Baba、Keisuke Kosumi, Daichi Nomoto, Kazuo Okadome, Taisuke Yagi, Yuki Kiyozumi, Kojiro Eto, Yukiharu Hiyoshi, Takatsugu Ishimoto, Masaaki Iwatsuki, Shiro Iwagami, Yuji Miyamoto, Naoya Yoshida, Hideo Baba
  • Organizer: The International Society for Disease of the Esophagus(ISDE)
  • Int'l Joint Research