1. Genetic and epigenetic alterations in normal tissues have differential impacts on cancer risk among tissues
- Author
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Naoko Hattori, Satoshi Yamashita, Ichiro Oda, Hadrien Charvat, Takamasa Takahashi, Taichi Shimazu, Yasuo Kakugawa, Ming-Shiang Wu, Reiko Nagano, Naoko Iida, Hideyuki Takeshima, Takayoshi Kishino, Takeshi Nakajima, Masahiro Maeda, Toshikazu Ushijima, Yi-Chia Lee, and Shoichiro Tsugane
- Subjects
0301 basic medicine ,Male ,Esophageal Neoplasms ,Physiology ,medicine.disease_cause ,Epigenesis, Genetic ,Helicobacter Infections ,03 medical and health sciences ,Mutation Rate ,Risk Factors ,Stomach Neoplasms ,Biomarkers, Tumor ,Medicine ,Humans ,Point Mutation ,Epigenetics ,Esophagus ,Multidisciplinary ,Cancer prevention ,business.industry ,Stomach ,Cancer ,Odds ratio ,DNA Methylation ,Biological Sciences ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Transcription Factor AP-2 ,Gastric Mucosa ,DNA methylation ,Carcinoma, Squamous Cell ,Female ,Esophageal Squamous Cell Carcinoma ,business ,Carcinogenesis ,Genome-Wide Association Study - Abstract
Genetic and epigenetic alterations are both involved in carcinogenesis, and their low-level accumulation in normal tissues constitutes cancer risk. However, their relative importance has never been examined, as measurement of low-level mutations has been difficult. Here, we measured low-level accumulations of genetic and epigenetic alterations in normal tissues with low, intermediate, and high cancer risk and analyzed their relative effects on cancer risk in the esophagus and stomach. Accumulation of genetic alterations, estimated as a frequency of rare base substitution mutations, significantly increased according to cancer risk in esophageal mucosae, but not in gastric mucosae. The mutation patterns reflected the exposure to lifestyle risk factors. In contrast, the accumulation of epigenetic alterations, measured as DNA methylation levels of marker genes, significantly increased according to cancer risk in both tissues. Patients with cancer (high-risk individuals) were precisely discriminated from healthy individuals with exposure to risk factors (intermediate-risk individuals) by a combination of alterations in the esophagus (odds ratio, 18.2; 95% confidence interval, 3.69–89.9) and by only epigenetic alterations in the stomach (odds ratio, 7.67; 95% confidence interval, 2.52–23.3). The relative importance of epigenetic alterations upon genetic alterations was 1.04 in the esophagus and 2.31 in the stomach. The differential impacts among tissues will be critically important for effective cancer prevention and precision cancer risk diagnosis.
- Published
- 2018