Division of Carcinogenesis and Cancer Prevention(Environmental Carcinogenesis and Prevention Group)

Yukari Totsuka, Michihiro Mutoh, Ken-ichi Yoshioka, Gen Fujii, Sachiko Dobashi, Masanori Goto, Haruna Sato, Nozomi Akiba, Yuya Maesako, Syouma Kamio, Akane Zenke, Takahiro Hamoya, Shuuya Tamura, Yurie Kurokawa, Maiko Takahashi, Yusuke Minakawa, Atsuhiro Shimizu, Yusuke Matsuno

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.

Research activities

1.Exploration of cancer etiology using whole genome/exome analysis and comprehensive DNA adduct analysis

It is well known that environmental factors contribute substantially to human cancer development in cooperation with genetic factors. Global mutation analysis is a useful way to confirm which candidate substances contribute to human cancer development. Recently, chemical substances have been shown to exhibit characteristic mutational signatures. Comparing mutational signatures derived from chemicals with those derived from human cancers can lead to the clarification of genome-wide mutation profiles in the chemical-human cancer relationship. Dichloromethane (DCM) and 1,2-dichloropropane (DCP) have been suggested to be responsible for occupational cholangiocarcinoma by an epidemiological study. Based on the whole exome sequencing analysis, huge numbers of somatic mutations were observed in printing worker cases, and the C:G to T:A transition with strand-bias was predominant. In addition, this C:G to T:A transition mostly occurred at the unique trinucleotide sequence contexts. By comparison with the mutational profile of 1,2-DCP observed in Salmonella strains, the three letter mutational pattern partially corresponded to that of the printing workers'cholangiocarcinoma. From these observations, it is suggested that 1,2-DCP might contribute to the carcinogenesis of cholangiocarcinoma among printing industry workers, at least in some part.

2.Genome destabilization and the associated hypermutation induction

Microsatellite instability (MSI) is widely found in mismatch repair (MMR)-deficient cancer cells in association with increased levels of mutations. However, it remains elusive how MSI is induced and contributes to cancer development. Here, we showed that DNA-replication stress triggers MSI induction coupled with hypermutation by low fidelity translesion synthesis (TLS) polymerases. Stressed replication forks in MMR-deficient cells are protected from lasting DNA double-strand breaks by PolQ-mediated repair, which enables to suppress chromosomal instability but alternatively causes MSI. In response to replication stress, replication-fork polymerase PolD was dissociated; instead, multiple error-prone TLS polymerases were induced, contributing to a hypermutagenic background with no proofreading in MMR deficient background.

3.Prevention of colorectal cancer

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 animal models of FAP.

Education

Ten undergraduate and graduate students in local universities worked as trainees in our lab and had cancer research training.

Future prospect

Explore the novel cancer etiology using whole genome analysis and comprehensive DNA adduct analysis

Establish a novel cancer prevention strategy based on the exploration of cancer etiology and mechanisms

Develop novel candidates for cancer chemopreventive agents and aim for their practical application

List of papers published in 2016

Journal

1.Hori M, Onaya H, Hiraoka N, Yamaji T, Kobayashi H, Takahashi M, Mutoh M, Shimada K, Nakagama H. Evaluation of the degree of pancreatic fatty infiltration by area-based assessment of CT images: comparison with histopathology-based and CT attenuation index-based assessments. Jpn J Radiol, 34:667-676, 2016

2.Minakawa Y, Atsumi Y, Shinohara A, Murakami Y, Yoshioka K-I. Gamma-irradiated quiescent cells repair directly induced double-strand breaks but accumulate persistent double-strand breaks during subsequent DNA replication. Genes Cells, 21:789-797, 2016

3.Ishikawa H, Mutoh M, Iwama T, Suzuki S, Abe T, Takeuchi Y, Nakamura T, Ezoe Y, Fujii G, Wakabayashi K, Nakajima T, Sakai T. Endoscopic management of familial adenomatous polyposis in patients refusing colectomy. Endoscopy, 48:51-55, 2016

4.Nakamura T, Ishikawa H, Mutoh M, Wakabayashi K, Kawano A, Sakai T, Matsuura N. Coffee prevents proximal colorectal adenomas in Japanese men: a prospective cohort study. Eur J Cancer Prev, 25:388-394, 2016

5.Hamoya T, Fujii G, Miyamoto S, Takahashi M, Totsuka Y, Wakabayashi K, Toshima J, Mutoh M. Effects of NSAIDs on the risk factors of colorectal cancer: a mini review. Genes Environ, 38:6, 2016

6.Miyamoto S, Terasaki M, Ishigamori R, Fujii G, Mutoh M. Prospective targets for colon cancer prevention: from basic research, epidemiology and clinical trial. J Dig Cancer Rep, 4:64-76, 2016

7.Onuma W, Tomono S, Miyamoto S, Fujii G, Hamoya T, Fujimoto K, Miyoshi N, Fukai F, Wakabayashi K, Mutoh M. Irsogladine maleate, a gastric mucosal protectant, suppresses intestinal polyp development in Apc-mutant mice. Oncotarget, 7:8640-8652, 2016

8.Imaoka T, Nishimura M, Daino K, Morioka T, Nishimura Y, Uemura H, Akimoto K, Furukawa Y, Fukushi M, Wakabayashi K, Mutoh M, Shimada Y. A Rat Model to Study the Effects of Diet-Induced Obesity on Radiation-Induced Mammary Carcinogenesis. Radiat Res, 185:505-515, 2016

9.Inoki K, Nakajima T, Sekine S, Sugano K, Tsukamoto S, Yamada M, Mutoh M, Sakamoto T, Matsuda T, Sekiguchi M, Ushiama M, Yoshida T, Sakamoto H, Kanemitsu Y, Saito Y. Depressed-type submucosal invasive colorectal cancer in a patient with Lynch syndrome diagnosed using short-interval colonoscopy. Dig Endosc, 28:749-754, 2016

10.Hori M, Mutoh M, Imai T, Nakagama H, Takahashi M. Possible involvement of pancreatic fatty infiltration in pancreatic carcinogenesis. JOP, 17:166-175, 2016

11.Mimaki S, Totsuka Y, Suzuki Y, Nakai C, Goto M, Kojima M, Arakawa H, Takemura S, Tanaka S, Marubashi S, Kinoshita M, Matsuda T, Shibata T, Nakagama H, Ochiai A, Kubo S, Nakamori S, Esumi H, Tsuchihara K. Hypermutation and unique mutational signatures of occupational cholangiocarcinoma in printing workers exposed to haloalkanes. Carcinogenesis, 37:817-826, 2016