Exploration of cancer etiology using whole genome/exome analysis and comprehensive DNA adduct analysis
Thursday 9 June - 11:00-11:20
photo intervenant Hitoshi NAKAGAMA
President, National Cancer Center (NCC), Tokyo, Japan

Hitoshi Nakagama graduated from the University of Tokyo in 1982 and received his MD from the university of Tokyo in 1991. He then moved to the United States and joined the Center for Cancer Research, MIT, and worked as a postdoctoral fellow on the functional analysis of the tumour suppressor gene, WT1, with Professor David Housman. After returning to Japan in 1995, he took up a position as Section head, Carcinogenesis Division, National Cancer Center Research Institute (NCCRI), and then became Chief, Biochemistry Division (1997), Deputy Director (2007), and Director of NCCRI in 2011. From April 1, 2016, he now serves as President of the National Cancer Center. He has long been working on animal cancer models of colon carcinogenesis induced by various environmental carcinogens and on the DNA adductome to elucidate genetic and epigenetic modifications which play pivotal roles in driving cancer development. He also identified several tumour suppressive microRNAs regulating cell cycle arrest and/or apoptosis after exposure to environmental damage, and proved that these tumour suppressive microRNAs are inactivated during colon carcinogenesis, including in the phase of liver metastasis. He is currently working on the application of exosomal microRNA in the early detection of various cancers.

It is well known that environmental factors contribute substantially to human cancer development in cooperation with genetic factors. Environmental mutagenic/carcinogenic compounds form DNA adducts and induce mutations in the genome. Recently, whole genome/exome sequencing analyses of human cancers have revealed the presence of characteristic and contextual mutation patterns, so-called “mutational signatures”, in various types of cancers. Since mutational signatures can reflect the etiology of cancers, identifying DNA adducts that are directly responsible for mutational signatures is an ideal way to elucidate environmental causes of individual cancers.
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 when non-biased global mutations were analyzed using whole genome/exome sequencing of mammalian cells and model organisms that were exposed to chemicals. 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.
Recently, we explored cholangiocarcinoma in printing industry workers. 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 such as GpCpY and NpCpY. 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.
On the other hand, we adopted comprehensive DNA adduct analysis (DNA adductome analysis) using LC-TOF-MS to explore DNA adducts that contribute to cancer development. We found for the first time that N2-(3,4,5,6-tetrahydro-2H-pyran-2-yl) deoxyguanosine, derived from N-nitrosopiperidine (NPIP), can be an etiological factor for esophageal cancer in regions of China. Mutational profiles induced by NPIP and somatic mutation profiles of esophageal cancer patients in these areas are also being investigated.
By using genome-wide analysis and DNA adductome analysis fused together, the novel etiology of human cancer can be unveiled.