High-definition CpG methylation of novel genes in gastric carcinogenesis identified by next-generation sequencing

Authors

Jorge L. Sepulveda, Columbia University in the City of New York
Jorge L. Gutierrez-Pajares, Columbia University in the City of New York
Aesis Luna, Columbia University in the City of New York
Yuan Yao, University of Pennsylvania
John W. Tobias, University of Pennsylvania Perelman School of Medicine
Steven Thomas, Columbia University in the City of New York
Yanghee Woo, Columbia University in the City of New York
Federico Giorgi, Columbia University in the City of New York
Elena V. Komissarova, Columbia University in the City of New York
Andrea Califano, Columbia University in the City of New York
Timothy C. Wang, Columbia University in the City of New York
Antonia R. Sepulveda, Columbia University in the City of New York

Document Type

Journal Article

Publication Date

2-1-2016

Journal

Modern Pathology

Volume

29

Issue

2

DOI

10.1038/modpathol.2015.144

Abstract

© 2016 USCAP, Inc All rights reserved. Gastric cancers are the most frequent gastric malignancy and usually arise in the sequence of Helicobacter pylori-associated chronic gastritis. CpG methylation is a central mechanism of epigenetic gene regulation affecting cancer-related genes, and occurs early in gastric carcinogenesis. DNA samples from non-metaplastic gastric mucosa with variable levels of gastritis (non-metaplastic mucosa), intestinal metaplasia, or gastric cancer were screened with methylation arrays for CpG methylation of cancer-related genes and 30 gene targets were further characterized by high-definition bisulfite next-generation sequencing. In addition, data from The Cancer Genome Atlas were analyzed for correlation of methylation with gene expression. Overall, 13 genes had significantly increased CpG methylation in gastric cancer vs non-metaplastic mucosa (BRINP1, CDH11, CHFR, EPHA5, EPHA7, FGF2, FLI1, GALR1, HS3ST2, PDGFRA, SEZ6L, SGCE, and SNRPN). Further, most of these genes had corresponding reduced expression levels in gastric cancer compared with intestinal metaplasia, including novel hypermethylated genes in gastric cancer (FLI1, GALR1, SGCE, and SNRPN), suggesting that they may regulate neoplastic transformation from non-malignant intestinal metaplasia to cancer. Our data suggest a tumor-suppressor role for FLI1 in gastric cancer, consistent with recently reported data in breast cancer. For the genes with strongest methylation/expression correlation, namely FLI1, the expression was lowest in microsatellite-unstable tumors compared with other gastric cancer molecular subtypes. Importantly, reduced expression of hypermethylated BRINP1 and SGCE was significantly associated with favorable survival in gastric cancer. In summary, we report novel methylation gene targets that may have functional roles in discrete stages of gastric carcinogenesis and may serve as biomarkers for diagnosis and prognosis of gastric cancer.

APA Citation

Sepulveda, J., Gutierrez-Pajares, J., Luna, A., Yao, Y., Tobias, J., Thomas, S., Woo, Y., Giorgi, F., Komissarova, E., Califano, A., Wang, T., & Sepulveda, A. (2016). High-definition CpG methylation of novel genes in gastric carcinogenesis identified by next-generation sequencing. Modern Pathology, 29 (2). http://dx.doi.org/10.1038/modpathol.2015.144