2018 Fiscal Year Final Research Report

Identification of marker genes and pathways specific to precancerous duodenal adenomas and early stage adenocarcinomas.

Research Project

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Project/Area Number	17K15925
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Multi-year Fund
Research Field	Gastroenterology
Research Institution	The University of Tokyo
Principal Investigator	Sakaguchi Yoshiki 東京大学, 医学部附属病院, 助教 (20791445)
Research Collaborator	Yamamichi Nobutake Tomida Shuta
Project Period (FY)	2017-04-01 – 2019-03-31
Keywords	十二指腸上皮性腫瘍 / GSEA / 網羅的遺伝子発現解析 / Wnt/βcatenin pathway
Outline of Final Research Achievements	Gene expression profiling was performed in 4 pairs of duodenal　adenoma/adenocarcinomas and corresponding matched normal tissue. 626 probes consistently demonstrated over a 2-fold expression difference between tumor-normal pairs. GSEA demonstrated a strong association between duodenal adenoma/adenocarcinomas with colorectal adenomas (p<10-5) and gene expression patterns seen after APC gene knockout (p<10-5), suggesting that the Wnt/β-catenin pathway plays a crucial role in the carcinogenesis of these neoplasms. Immunohistochemical staining of an independent group of duodenal adenomas confirmed over-accumulation of β-catenin. In conclusion, precancerous duodenal adenomas and early-stage adenocarcinomas demonstrate gene expression characteristics with a strong resemblance to colorectal adenomas. The results of this study strongly suggest that up-regulation of the Wnt/β-catenin pathway is the major factor involved in the initial stages of the carcinogenesis of duodenal adenocarcinomas.
Free Research Field	消化器内科
Academic Significance and Societal Importance of the Research Achievements	本研究は十二指腸上皮性腫瘍の網羅的遺伝子発現解析、バイオインフォマティクス解析を通して、世界で初めて十二指腸上皮性腫瘍と大腸腺腫の類似性を示した。現在は十二指腸上皮性腫瘍に対する臨床上の治療ガイドラインも定まっておらず、今後十二指腸上皮性腫瘍に対する治療方針に寄与する結果であり、臨床的な意義が高い。また、Wnt/βcatenin pathwayが十二指腸上皮性腫瘍の形成に強く関与していることも初めて示した。最後に、十二指腸癌の発現プロファイルを明らかにすることにより、今後drug repositioningによる化学療法レジメンの予測モデル樹立に向けて基盤を形成することに成功し、意義が高い。