Novel epigenetic markers for gastric cancer risk stratification in individuals after Helicobacter pylori eradication
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The risk stratification of healthy individuals after Helicobacter pylori eradication is an urgent issue. The assessment of aberrant DNA methylation accumulated in gastric tissues with normal appearance, which can reflect overall epigenomic damage, is a promising strategy. We aimed to establish novel epigenetic cancer risk markers for H. pylori-eradicated individuals.
Gastric mucosa was collected from eight healthy volunteers without H. pylori infection (G1), 75 healthy individuals with gastric atrophy (G2), and 94 gastric cancer patients (G3) after H. pylori eradication. Genome-wide analysis was conducted using Infinium 450 K and differentially methylated probes were screened using large difference and iEVORA-based methods. Bisulfite pyrosequencing was used for validation.
Screening, using 8 G1, 12 G2, and 12 G3 samples, isolated 57 candidates unmethylated in G1 and differentially methylated in G3 compared with G2. Validation for nine candidate markers (FLT3, LINC00643, RPRM, JAM2, ELMO1, BHLHE22, RIMS1, GUSBP5, and ZNF3) in 63 G2 and 82 G3 samples showed that all of them had significantly higher methylation levels in G3 than in G2 (P < 0.0001). Their methylation levels were highly correlated, which indicated that they reflect overall epigenomic damage. The candidates had sufficient performance (AUC: 0.70–0. 80) and high odds ratios (5.43–23.41), some of which were superior to a previous marker, miR-124a-3. The methylation levels of our novel markers were not associated with gastric atrophy, gender, or age.
Novel epigenetic markers for gastric cancer risk optimized for H. pylori-eradicated individuals were established.
KeywordsEpigenetics Cancer risk marker DNA methylation Gastric cancer Helicobacter pylori
The authors are grateful to Drs. Y. Kakugawa, Y. Otake and T. Gotoda for sample and data acquisition, and Dr. N. Hattori for her advice, and Drs. K. Ichimura, Y. Matsushita, and M. Kitahara of Division of Brain Tumor Translational Research in National Cancer Center Research Institute for their technical assistance with the experiments.
Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and Development, AMED (15ck0106023h0002, 16ck0106023h0003, 17ck0106267h0001).
Compliance with ethical standards
Conflict of interest
MM and TU made a joint patent application with Sysmex Corporation for identified epigenetic markers.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent or substitute for it was obtained from all patients for being included in the study.
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