Molecular elucidation of tumor progression of adenoid cystic carcinoma(Fostering Joint International Research)

2019 Fiscal Year Final Research Report

• Project/Area Number: 15KK0334
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: Otorhinolaryngology
• Research Institution: The University of Tokyo
• Principal Investigator: Ando Mizuo 東京大学, 医学部附属病院, 講師 (60511467)
• Project Period (FY): 2016 – 2019
• Keywords: エピゲノム / 腺様嚢胞癌 / 扁平上皮癌 / 転写開始点

Outline of Final Research Achievements

Although DNA methylation at promoter-associated CpG islands is well known to be correlated with gene repression, genome-wide studies utilizing massively parallel sequencing have described a role for DNA methylation outside these well-described CpG sites and thus expanded the focus of epigenetically mediated transcriptional regulation to much larger regions of interest.
Here we describe a tumor-specific shift in association of transcriptional repression from DNA methylation at conventional promoter regions in normal tissue, to cancer-specific transcriptional repression associated with broad repressive chromatin marks and DNA methylation at transcriptional start sites (TSSs) regardless of CpG island presence. These findings are complemented by identification of a hypermethylation phenotype in HPV-related oropharyngeal cancer, characterized by MYC pathway activation.

Free Research Field

癌ゲノム

Academic Significance and Societal Importance of the Research Achievements

HPV関連中咽頭癌の腫瘍組織は正常組織とは異なるDNAメチル化状態を示し、従来注目されてきた遺伝子の調節領域である「プロモーター領域」よりも、むしろ「転写開始点」におけるDNAメチル化状態の変化が遺伝子発現と強く関連していることを突き止めた。この結果は、発癌に繋がるエピゲノム異常の解明において、転写開始点への注目を促す画期的な発見である。また、Mycによるエピゲノム調節機構は過去の基礎的研究でも報告されていたが、実際のHPV関連中咽頭癌において示された初めての報告となる。これらの成果は、HPV関連中咽頭癌の病態解明に貢献し、治療の最適化の実現に役立つものと期待される。