Author:
Yamashita Satoshi,Kishino Takayoshi,Takahashi Takamasa,Shimazu Taichi,Charvat Hadrien,Kakugawa Yasuo,Nakajima Takeshi,Lee Yi-Chia,Iida Naoko,Maeda Masahiro,Hattori Naoko,Takeshima Hideyuki,Nagano Reiko,Oda Ichiro,Tsugane Shoichiro,Wu Ming-Shiang,Ushijima Toshikazu
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.
Funder
Japan Agency for Medical Research and Development
The Ministry of Education, Culture, Sports, Science, and Technology, Japan
The National Cancer Center Research and Development Fund
The Ministry of Science and Technology, R. O. C.
Publisher
Proceedings of the National Academy of Sciences