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Home > Organization > Divisions and Independent Research Units > Group for Development of Molecular diagnostics and Individualized Therapy > Division of Epigenomics

Division of Epigenomics

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Overview

This Division analyzes mechanisms of how cancer develops without alterations in DNA sequences, and develops applications from these mechanisms for cancer prevention, diagnosis, and therapy.  Back in 1997, we developed one the earliest genome-wide screening methods for differences in DNA methylation, methylation-sensitive representational difference analysis (MS-RDA) (Ushijima et al., 1997, Ushijima, 2005).  Using this method, we isolated aberrant DNA methylation in a variety of cancers, and identified a tumor-suppressor gene in gastric cancer (Kaneda et al., 2004).  In neuroblastoma, predominantly a pediatric cancer, we identified a prognostic marker, MYCN amplification, whose accuracy exceeds that of the clinically used molecular marker, (Abe et al., 2005).

 

Epigenetic field for cancerization and its use for cancer risk diagnosis

The above research in gastric cancer led to the discovery that aberrant DNA methylation is already present in normal-appearing tissues long before a cancer develops, namely an epigenetic field for cancerization (Maekita et al., 2006, Ushijima, 2007).  We confirmed that the level of accumulation of aberrant DNA methylation is correlated with cancer risk (Nakajima et al., 2006).  We conducted a multicenter prospective study to bring the finding into clinical practice for cancer risk diagnosis, and demonstrated for the first time by a multicenter prospective study that the accumulation level of aberrant DNA methylation can predict cancer risk (Asada et al., 2015, Maeda et al., 2017).  Now, we are conducting another multicenter prospective study to demonstrate that epigenetic cancer risk diagnosis is useful even among healthy people after eradication of Helicobacter pylori.  We hope that we will be able to offer accurate risk estimation in this population in the near future. 

 

Identification of mechanisms of how chronic inflammation induces aberrant DNA methylation and its application to cancer prevention

We have been investigating into how Helicobacter pylori infection induces aberrant DNA methylation. We demonstrated that, not Helicobacter pylori itself, but chronic inflammation triggered by it was responsible for methylation induction (Niwa et al., 2010), and that a specific type of inflammation is important (Hur et al., 2011). Such inflammation induces both decreased expression of an enzyme to erase DNA methylation and increased activity of enzymes to put DNA methylation (Takeshima et al., 2020). We previously demonstrated that suppression of aberrant DNA methylation can reduce gastric cancer incidence in Mongolian gerbils(Niwa et al., 2013). We are now trying to find a cancer prevention method that can be applied to man.

 

Novel predictive markers and their mechanisms of action

We have traditional and cutting-edge technologies for genome-wide DNA methylation analysis.  Using these technologies, and in collaboration with our hospitals, we isolated a DNA methylation marker that predicts pathological complete response of HER2-positive breast cancers to trastuzumab and chemotherapy (Fujii et al., 2017), and a marker that predicts response of esophageal squamous cell carcinoma to definitive chemoradiotherapy (Iwabu et al., 2019).  Now, to develop more effective therapeutic approaches, we are investigating the mechanisms of how these markers predict well. 

 

Development of epigenetic therapy

Reversal of aberrant DNA methylation by DNA demethylating drugs is clinically used for treatment of hematological tumors.  This Division showed that DNA demethylating drugs can be used to restore sensitivity of gastric cancer cells to cytotoxic drugs (Moro et al., 2019).  We also developed a novel high-throughput screening system for DNA demethylating agents (Okochi-Takada et al., 2018), and isolated DNA demethylating agents that are expected to have less toxicity (Hattori et al., 2019).  In addition, we demonstrated that epigenetic therapy targets not only cancer cells but also the surrounding cells that support cancer cells, namely cancer-associated fibroblasts (Maeda et al., 2019).  Targeting multiple genes in multiple cell types can become one of the next strategies of cancer therapy.