Abstract LB-157: Demonstration of the usefulness of an epigenetic cancer risk marker by a multicenter prospective cohort study
Authors: Maeda Masahiro , Asada Kiyoshi , Nakajima Takeshi , Shimazu Taichi , Yamamichi Nobutake , Maekita Takao , Yokoi Chizu , Oda Ichiro , Ando Takayuki , Yoshida Takeichi , Nanjo Sohachi , Fujishiro Mitsuhiro , Gotoda Takuji , Ichinose Masao , Ushijima Toshikazu 
Published: August 2015

Abstract
An epigenetic cancer risk marker is a promising cancer risk marker that can reflect past exposure to various environmental factors, such as chronic inflammation, unlike single nucleotide polymorphism cancer risk markers. Cross-sectional studies have shown that the degree of accumulation of aberrant DNA methylation in normal-appearing tissues was associated with risk of some types of cancer, especially gastric cancer [Ushijima et al., Clin Cancer Res,2,143,2012]. In this study, we aimed to demonstrate that cancer risk can be predicted by an epigenetic cancer risk marker. For this purpose, we decided to predict the risk of metachronous gastric cancer after endoscopic resection because we could expect a sufficient number of events in three years.
826 patients with early gastric cancer, aged 40-80 years, who had undergone endoscopic resection were enrolled. If the patients were infected with Helicobacter. pylori (H. pylori), a potent inducer of aberrant DNA methylation, eradication was performed. For all enrolled patients, methylation levels of three preselected genes, miR-124a-3, EMX1 and NKX6-1, were measured by quantitative methylation-specific PCR. Patients were followed up annually by endoscopy to detect a metachronous gastric cancer. Authentic metachronous gastric cancers were defined as cancers excluding those detected within 1 year after the enrollment.
782 of 826 patients had at least one follow-up, with a median follow-up of 2.97 years. Authentic metachronous gastric cancers developed in 66 patients: 29, 16 and 21 patients at 1-2, 2-3 and ≥3 years after the enrollment, respectively. The highest quartile of the miR-124a-3 methylation level had a significantly high HR in univariate analysis (95% CI) [2.17 (1.07 to 4.41); p = 0.032] and adjusted HR in multivariate analysis [2.30 (1.03 to 5.10); p = 0.042] of developing authentic metachronous gastric cancers. Similar trends were observed for EMX1 and NKX6-1.
This study, for the first time, demonstrated the usefulness of an epigenetic cancer risk marker by a multicenter prospective cohort study [Asada et al., Gut,1,171,2014]. It is speculated that DNA methylation is accumulated both in stem and differentiated cells of gastric mucosa, and that methylation in stem cells can permanently persist, even after H. pylori infection discontinues, and that DNA methylation accumulated in stem cells is correlated with cancer risk [Ushijima et al., J Gastroenterol,3,161,2006].
Citation Format: Masahiro Maeda, Kiyoshi Asada, Takeshi Nakajima, Taichi Shimazu, Nobutake Yamamichi, Takao Maekita, Chizu Yokoi, Ichiro Oda, Takayuki Ando, Takeichi Yoshida, Sohachi Nanjo, Mitsuhiro Fujishiro, Takuji Gotoda, Masao Ichinose, Toshikazu Ushijima. Demonstration of the usefulness of an epigenetic cancer risk marker by a multicenter prospective cohort study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-157. doi:10.1158/1538-7445.AM2015-LB-157