Identification of novel tumor-suppressor genes by Outlier approach

2013 Fiscal Year Final Research Report

• Project/Area Number: 23710227
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Medical genome science
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: TAKESHIMA Hideyuki 独立行政法人国立がん研究センター, 研究所, 研究員 (40432497)
• Project Period (FY): 2011 – 2013
• Keywords: エピジェネティクス / DNAメチル化 / がん抑制遺伝子 / サイレンシング / マイクロアレイ

Research Abstract

Aberrant DNA methylation of promoter CpG islands (CGIs) is deeply involved in human carcinogenesis. Although hundreds to thousands of genes are aberrantly methylated in cancer cells, the majority is methylated as a consequence of carcinogenesis, and it is difficult to identify tumor-suppressor genes (TSGs) from numerous methylated genes. In this study, we developed a novel method to identify TSGs based on our previous findings that genes with RNA polymerase II (Pol II) in normal cells are resistant to aberrant methylation induction and that known TSGs were methylated in cancers against this general rule. First, we identified 280 methylation-sensitive genes in human breast cancers. From these genes, 14 genes methylated against the general rule (outlier genes) were isolated by analyzing Pol II binding in normal cells. Among these genes, DZIP1 was a novel TSG, and FBN2 and HOXA5 were known TSGs. These results showed that TSGs can be efficiently identified by this approach.

Research Products

• [Journal Article] Development of a novel approach, the epigenome-based outlier approach, to identify tumor-suppressor genes silenced by aberrant DNA methylation (2012)
  • Author(s): Kikuyama, M, Takeshima, H, Kinoshita, T, Okochi-Takada, E, Wakabayashi, M, Akashi-Tanaka, S, Ogawa, T, Seto, Y and Ushijima, T
  • Journal Title: Cancer Lett. Volume: 322 Pages: 204-212
  • Peer Reviewed
• [Journal Article] Effects of genome architecture and epigenetic factors on susceptibility of promoter CpG islands to aberrant DNA methylation induction (2011)
  • Author(s): Takeshima, H, Yamashita, S, Shimazu, T and Ushijima, T
  • Journal Title: Genomics Volume: 98 Pages: 182-188
  • Peer Reviewed
• [Presentation] The outlier approach discriminates drivers from passengers among genes methylated in cancer (2012)
  • Author(s): Kikuyama, M, Takeshima, H, Kinoshita, T, Okochi-Takada, E, Wakabayashi, M, Akashi-Tanaka, S, Ogawa, T, Seto, Y and Ushijima, T
  • Organizer: AACR annual meeting 2012
  • Place of Presentation: シカゴ(米国)
  • Year and Date: 2012-04-03
• [Presentation] ゲノム構造及びエピジェネティック因子は独立してメチル化異常誘発に対する感受性に影響する (2011)
  • Author(s): 竹島秀幸, 山下聡, 島津太一 and 牛島俊和
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-03
• [Presentation] エピジェネティックに不活化された遺伝子の中からがん抑制遺伝子を選別する方法の開発 (2011)
  • Author(s): 菊山みずほ, 竹島秀幸, 大河内(髙田)江里子, 明石(田中)定子, 木下貴之, 小川利久, 瀬戸泰之 and 牛島俊和
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-03
• [Presentation] 繰り返し配列LINE及びSINEはDNAメチル化異常誘発に対する感受性を与える (2011)
  • Author(s): 竹島秀幸, 山下聡, 島津太一 and 牛島俊和
  • Organizer: 第5回日本エピジェネティクス研究会年会
  • Place of Presentation: 熊本
  • Year and Date: 2011-05-20
• [Presentation] エピジェネティックに不活化された遺伝子の中からがん抑制遺伝子を選別する方法の開発 (2011)
  • Author(s): 菊山みずほ, 竹島秀幸, 大河内(髙田)江里子, 小川利久, 瀬戸泰之 and 牛島俊和
  • Organizer: 第5回日本エピジェネティクス研究会年会
  • Place of Presentation: 熊本
  • Year and Date: 2011-05-20