Abstract 695: Relative importance between DNA methylation and mutation in nonmalignant tissue for cancer risk

Abstract Cancer risk is correlated with the accumulation level of genetic (mutation) and epigenetic alterations (DNA methylation). Analysis of these alterations in nonmalignant tissue contributes to assessing cancer risk and to revealing environmental factors that induce the alterations. DNA methylation can be readily measured due to its high accumulation levels, while on the other hand, it is difficult to measure accumulation levels of mutations because of their rarity. To detect rare point mutations accurately and inexpensively, we developed a novel next generation sequencing (NGS) method, EcoSeq [Ueda, PNAS, 119:e2123241119, 2022]. Here, using EcoSeq, we aimed to evaluate the impact of DNA methylation and mutation for gastric cancer risk, and the mutational signatures of H. pylori (HP) infection, which is a mutagen for gastric cancer. Nonmalignant gastric mucosae were obtained from G1 (low risk; never infected with HP), G2 (intermediate; healthy people after HP eradication) and G3 (high; cancer patients after HP eradication). The mutation frequency was slightly increased by history of HP infection (p=<0.0001, G1vsG2), but not associated with cancer risk (p=0.50, G2vsG3). On the other hand, the DNA methylation level of miR124a-3 was strongly correlated with cancer risk (p<0.0001, G1vsG2; 0.00069, G2vsG3). Mutational signatures of SBS39 were observed in G2 and G3. These results showed that DNA methylation was more useful for assessing gastric cancer risk than point mutation frequency, and suggested that SBS39 is due to HP infection. Citation Format: Harumi Yamada, Satoshi Yamashita, Yu-Yu Liu, Toshikazu Ushijima. Relative importance between DNA methylation and mutation in nonmalignant tissue for cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 695.