Annual Report 2019
Division of Carcinogenesis and Cancer Prevention
(Environmental Carcinogenesis and Cancer Prevention Group)
Yukari Totsuka, Yutaka Shoji, Haruna Sato, Keita Iwamura, Yumi Miyamoto, Tomoko Makabe, Michihiro Mutoh, Gen Fujii, Takahiro Hamoya, Yui Matsuzawa, Kohei Miki, Takahiro Teruya, Ken-ichi Yoshioka, Yusuke Matsuno, Haruka Fujimori, Mai Hyodo
Introduction
Cancer is a disease associated with aging and environmental risk factors. It is well known that chemical substances form DNA adducts, which are considered to be a ‘trigger’ of mutagenesis. As cancer risk elevates in association with aging, genomic destabilization frequently arises in the cells of the elderly, which is associated with the impairment of DNA repair functions. The aims of our research projects are exploration of novel cancer etiology via identification of DNA adducts that are important for human cancer development, and clarification of the mechanisms for genomic instability associated with aging. On the other hand, cancer chemoprevention is one of the preemptive approaches that is strongly expected to reduce cancer morbidity and mortality. We are working to develop novel candidates for cancer chemopreventive agents and aim for their practical application using the concept of drug repositioning.
The Team and What We Do
1) Exploration of cancer etiology using whole genome/exome analysis and comprehensive DNA adduct analysis. (Totsuka group)
2) Studying mechanistic aspects of genome destabilization and the associated effects on mutation induction and the clonal evolution. This group also studies mechanisms to maintain genome stability. (Yoshioka group)
3) Prevention of colorectal cancer. (Mutoh group)
Research activities
1. Exploration of cancer etiology using whole genome/exome analysis and comprehensive DNA adduct analysis (Totsuka group)
Esophageal cancer is prevalent in Cixian, China, but the etiology of this disease remains largely unknown. We explored this by conducting a DNA adductome analysis. N2-(3,4,5,6-tetrahydro-2H-pyran-2-yl)deoxyguanosine (THP-dG) was the major adduct detected in samples from esophageal cancer patients in Cixian. The precursor of THP-dG, N-nitrosopiperidine (NPIP), has been reported as a strong esophageal carcinogen in rats. We examined THP-dG in peripheral blood samples, and found that the adduct levels were significantly higher in high-incidence areas than in low-incidence areas. The NPIP-induced mutation spectrum was similar to that of esophageal cancer patients, which demonstrated weak correlation with THP-dG levels. These findings suggested that NPIP exposure is partly involved in the development of esophageal cancer in Cixian residents.
2. Senescence-associated risk elevation of genomic destabilization and the resulting clonal evolution (Yoshioka group)
Most cancers develop through genomic instability. However, it is still elusive how normal cells become subject to genomic destabilization and how genomic destabilization is associated with cancer development. Here we found that replication stress-associated DSBs are accumulated in a senescent cellular state, in which genomic destabilization risk is elevated. Since genomic destabilization is associated with mutation induction, this further leads to clonal evolution of cells abrogating their defense systems.
3. Prevention of colorectal cancer (Mutoh group)
Familial adenomatous polyposis (FAP) patients are a well-known high-risk group with colorectal cancer (CRC). We are evaluating the usefulness and safety of thorough endoscopic polypectomy and of cancer chemopreventive agents in FAP patients. Based on these findings, we are trying to clarify the underlying mechanism of colorectal carcinogenesis in a laboratory study. Moreover, we are searching for novel chemopreventive agents against CRC using a high-throughput screening approach and animal models of FAP.
Education
Eight graduate students in local universities worked as trainees in our lab and had cancer research training.
Future prospects
- Explore the novel cancer etiology using whole genome/exome analysis and comprehensive DNA adduct analysis
- Uncover the mechanisms for the formation of a cellular state with a higher risk of genomic destabilization and establish a strategy to prevent cancer through genome-stability maintenance.
- Develop novel candidates for cancer chemopreventive agents and aim for their practical application.