Discovery and validation of pan cancer epigenetic biomarkers

• Project/Area Number: 17K18366
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor diagnostics; Medical genome science
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Kaczkowski Bogumil 国立研究開発法人理化学研究所, 生命医科学研究センター, 研究員 (50648136)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: cancer / epi-genome / transcriptome / genome / DNA methylation / gene expression / translational research

Outline of Final Research Achievements

Despite decades of research, few cancer biomarkers are being used in clinics. Based on the assumption that DNA methylation is involved in stable, long-term regulation, we propose that differentially expressed genes that are caused by aberrant DNA methylation are optimal candidates for biomarkers. We performed computation analyses integrating publicly available transcriptomic and epigenomic data. We discovered 49 coding genes and 10 noncoding RNAs, which are upregulated in NSCLC lung cancer due to promoter hypomethylation. We also observed that multiple copies of the REP522 DNA repeat family are activated in lung cancer by DNA hypomethylation and histone modification. To study the link between DNA methylation and transcription more closely, we performed perturbation experiments, where normal cells were treated with a demethylating agent and histone deacetylase inhibitor. The perturbations were followed by gene expression profiling (CAGE), DNA methylation array, and single-cell C1-CAGE.

Academic Significance and Societal Importance of the Research Achievements

The results and data generated in the project help us to better understand the link between the aberrant epigenetic changes and the gene expression in cancer. This opens a way to uncover the theragnostic potential of epigenetically regulated genes in clinical cancer research.

Research Products

• [Journal Article] Integrative CAGE and DNA Methylation Profiling Identify Epigenetically Regulated Genes in NSCLC (2017)
  • Author(s): Horie M, Kaczkowski B, Ohshima M, Matsuzaki H, Noguchi S, Mikami Y, Lizio M, Itoh M, Kawaji H, Lassmann T, Carninci P, Hayashizaki Y, Forrest ARR, Takai D, Yamaguchi Y, Micke P, Saito A, Nagase T.
  • Journal Title: Mol Cancer Res. Volume: 15 Issue: 10 Pages: 1354-1365
  • DOI: 10.1158/1541-7786.mcr-17-0191
  • Peer Reviewed / Open Access / Int'l Joint Research