Cancer Genome Informatics
- Genome analysis of rare and intractable cancers
- Cancer heterogeneity and evolution of the cancer genome
- Early diagnosis for intractable cancers (especially pancreatic cancer)
- Cancer genome medicine
- Crosstalk between the microbiome and cancer
Study of the cancer genome for clinical applications
Cancer is considered to be fundamentally a genetic disease. We have performed multi-region sequencing of the genome in pancreatic cancer patients post-mortem and made a breakthrough discovery in cancer research, finding genomic heterogeneity and clonal evolution in cancers (Yachida et al., Nature 2010). We showed that tumor progression proceeds analogously to Darwinian evolution over the course of several decades, during which time multiple genomic alterations accumulate. Furthermore, cancer cells evolve resistance to treatment (e.g., anticancer drugs, molecular target drugs and immunotherapeutic drugs), and we are investigating the mechanisms that enable this resistance. Its heterogeneity and evolution/clonal selection make cancer a difficult disease to treat. Understanding cancer evolution (i.e., cancer’s continuous adaptation) is critical.
The impressive progress of comprehensive genomic analysis technology including next generation sequencers is changing cancer research. In order to deal with the increasing and enormous number of genomic and clinical information, experts in bioinformatics are key. I believe bioinformaticians will have an integral role in decision making on cancer treatments in the near future. Our laboratory is developing bioinformatics resources including training to contribute to other life science departments.
Lifestyle and demographics have a large influence on the effects of carcinogenic factors. To study their impact requires international collaborations. We are building these collaborations with special consideration for rare cancers. Recently, we have sequenced 172 ampullary carcinomas and identified a tumor suppressor gene, ELF3, as a driver of ampullary carcinoma (Figure 1). In addition, we conducted multi-region exome sequencing of an ampullary carcinoma using new technology (Glass Chip Macrodissection). This analysis demonstrated clonal evolution during ampullary cancer progression (Figure 2).
Figure1: Genomic Alterations of Ampullary Carcinomas
Figure2: Geographic Mapping of Subclones Based on Multi-Region Exome Sequencing and Proposed Clonal Evolution of an Ampullary Carcinoma with Low-Grade and High-Grade Intraepithelial Neoplasias
Circulating cell-free DNA (cfDNA) exists as small DNA fragments in blood. The assessment of mutations and copy number alterations in tumor-derived DNA in plasma cfDNA may provide a prognostic and diagnostic tool to assist decisions regarding optimal therapeutic strategies for cancer patients. This approach is less-invasive (“liquid biopsy”) and could overcome the problem of tumor heterogeneity. We are collaborating with companies for its clinical implementation.
Finally, we have been researching metagenomics and metabolomics of the human gut microbiome in collaboration with the National Cancer Center, Tokyo Institute of Technology and Keio University (Gut 2016). Our findings indicate that colorectal cancer should not only be considered a genetic disease but also a microbial disease.
