Format

Send to

Choose Destination
Mod Pathol. 2016 Feb;29(2):182-93. doi: 10.1038/modpathol.2015.144. Epub 2016 Jan 15.

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

Author information

1
Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
2
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
3
Department of Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
4
Department of Surgery, Columbia University, New York, NY, USA.
5
Department of Systems Biology, Columbia University, New York, NY, USA.
6
Department of Medicine, Division of Gastroenterology, Columbia University, New York, NY, USA.

Abstract

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.

PMID:
26769141
DOI:
10.1038/modpathol.2015.144
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center