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

• 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
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000)
• Keywords: エピゲノム / 腺様嚢胞癌 / 扁平上皮癌 / 転写開始点 / 癌ゲノム解析 / 中咽頭癌 / 癌 / ゲノム

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.

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。

Research Products

• [Int'l Joint Research] カリフォルニア大学サンディエゴ校(米国) (2016)
  • Year and Date: 2016-04-09
• [Journal Article] Rational genomic optimization of DNA detection for human papillomavirus type 16 in head and neck squamous cell carcinoma (2020)
  • Author(s): Saito Y, Favorov AV, Forman M, Ren S, Sakai A, Fukusumi T, Liu C, Sadat S, Ando M, Xu G, Khan Z, Pang J, Valsamakis A, Fisch KM, Califano JA.
  • Journal Title: Head & Neck Volume: 42 Issue: 4 Pages: 688-697
  • DOI: 10.1002/hed.26041
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers (2019)
  • Author(s): Ando Mizuo、Saito Yuki、et al.
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 2188-2188
  • DOI: 10.1038/s41467-019-09937-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mutation of chromatin regulators and focal hotspot alterations characterize human papillomavirus?positive oropharyngeal squamous cell carcinoma (2019)
  • Author(s): Haft Sunny、Ren Shuling、Xu Guorong、Mark Adam、Fisch Kathleen、Guo Theresa W.、Khan Zubair、Pang John、Ando Mizuo、Liu Chao、Sakai Akihiro、Fukusumi Takahito、Califano Joseph A.
  • Journal Title: Cancer Volume: 125 Issue: 14 Pages: 2423-2434
  • DOI: 10.1002/cncr.32068
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A novel splice variant of LOXL2 promotes progression of human papillomavirus?negative head and neck squamous cell carcinoma (2019)
  • Author(s): Liu Chao、Guo Theresa、Sakai Akihiro、Ren Shuling、Fukusumi Takahito、Ando Mizuo、Sadat Sayed、Saito Yuki、Califano Joseph A.
  • Journal Title: Cancer Volume: 126 Issue: 4 Pages: 737-748
  • DOI: 10.1002/cncr.32610
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Discovery and development of differentially methylated regions in human papillomavirus-related oropharyngeal squamous cell carcinoma (2018)
  • Author(s): Ren Shuling、Gaykalova Daria、Wang Jennifer、Guo Theresa、Danilova Ludmila、Favorov Alexander、Fertig Elana、Bishop Justin、Khan Zubair、Flam Emily、Wysocki Piotr T.、DeJong Peter、Ando Mizuo、Liu Chao、Sakai Akihiro、Fukusumi Takahito、Haft Sunny、Sadat Sayed、Califano Joseph A.
  • Journal Title: International Journal of Cancer Volume: 143 Issue: 10 Pages: 2425-2436
  • DOI: 10.1002/ijc.31778
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Characterization of Alternative Splicing Events in HPV-Negative Head and Neck Squamous Cell Carcinoma Identifies an Oncogenic DOCK5 Variant (2018)
  • Author(s): Liu Chao、Guo Theresa、Xu Guorong、Sakai Akihiro、Ren Shuling、Fukusumi Takahito、Ando Mizuo、Sadat Sayed、Saito Yuki、Khan Zubair、Fisch Kathleen M.、Califano Joseph
  • Journal Title: Clinical Cancer Research Volume: 20 Issue: 20 Pages: 5123-5132
  • DOI: 10.1158/1078-0432.ccr-18-0752
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] TheNOTCH4-HEY1 Pathway Induces Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma (2017)
  • Author(s): Fukusumi Takahito、Guo Theresa W.、Sakai Akihiro、Ando Mizuo、Ren Shuling、Haft Sunny、Liu Chao、Amornphimoltham Panomwat、Gutkind J. Silvio、Califano Joseph A.
  • Journal Title: Clinical Cancer Research Volume: 24 Issue: 3 Pages: 619-633
  • DOI: 10.1158/1078-0432.ccr-17-1366
  • Peer Reviewed / Int'l Joint Research
• [Presentation] HPV関連中咽頭癌のエピゲノム：DNAメチル化およびヒストン修飾のゲノムワイド解析 (2019)
  • Author(s): 安藤 瑞生、齊藤 祐毅、山岨 達也
  • Organizer: 第120回日本耳鼻咽喉科学会
• [Presentation] シンポジウム「トランスレーショナルリサーチはどう進んでいるか」：頭頸部癌クリニカルシーケンスの経験とゲノム医療時代の展望 (2019)
  • Author(s): 安藤瑞生
  • Organizer: 第43回日本頭頸部癌学会
• [Presentation] HPV関連中咽頭癌のエピゲノム解析：高DNAメチル化腫瘍の同定 (2018)
  • Author(s): 安藤瑞生、齊藤祐毅、山岨達也、Joseph A Califano
  • Organizer: 日本頭頸部癌学会
• [Remarks] ヒトパピローマウイルス（HPV）関連中咽頭がんのゲノム・エピゲノム異常の全体像を解明
  • URL: https://www.h.u-tokyo.ac.jp/press/20190517.html