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Chem Res Toxicol. 2019 Aug 19;32(8):1515-1527. doi: 10.1021/acs.chemrestox.9b00017. Epub 2019 Jul 9.

DNA Adductome Analysis Identifies N-Nitrosopiperidine Involved in the Etiology of Esophageal Cancer in Cixian, China.

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Division of Carcinogenesis & Prevention , National Cancer Center Research Institute , Tokyo 104-0045 , Japan.
Department of Public Health , Aichi Medical University School of Medicine , Nagakute 480-1195 , Japan.
Cancer Institute , The Fourth Hospital of Hebei Medical University/The Tumor Hospital of Hebei Province , Shijiazhuang 050011 , China.
Department of Bioinformatics , National Cancer Center Research Institute , Tokyo 104-0045 , Japan.
Division of Cancer Genomics , National Cancer Center Research Institute , Tokyo 104-0045 , Japan.
Research Center for Environmental Quality Management , Kyoto University , Shiga 520-0811 , Japan.
Department of Agricultural Chemistry , Tokyo University of Agriculture , Tokyo 156-8502 , Japan.
Cixian Cancer Hospital , Cixian 056500 , China.
Cancer Institute/Hospital , Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing 100021 , China.
Division of Prevention, Center for Public Health Sciences, National Cancer Center , Tokyo 104-0045 , Japan.
National Cancer Center , Tokyo 104-0045 , Japan.


Esophageal cancer is prevalent in Cixian, China, but the etiology of this disease remains largely unknown. Therefore, we explored this by conducting a DNA adductome analysis. Both tumorous and nontumorous tissues were collected from patients who underwent surgical procedures at Cixian Cancer Hospital and the Fourth Hospital of Hebei Medical University, which is in a low-incidence area. 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), exhibited a strong mutagenic activity under metabolic activation in the Ames test and a significant dose-dependent increase in mutation frequency during an in vivo mutagenicity test with guanine phosphoribosyltransferase (gpt) delta rats. The NPIP-induced mutation was dominated by A:T to C:G transversions, followed by G:C to A:T and A:T to G:C transitions, in the liver and esophagus of animal samples. A similar mutational pattern was observed in the mutational signature of esophageal cancer patients that 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.

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