title: High-definition CpG methylation of novel genes in gastric carcinogenesis identified by next-generation sequencing.
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.
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Sepulveda
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Gutierrez-Pajares
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
authors.forename: Aesis
authors.initials: A
authors.lastname: Luna
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Tobias
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Thomas
authors.affiliation: Department of Surgery, Columbia University, New York, NY, USA.
authors.forename: Yanghee
authors.initials: Y
authors.lastname: Woo
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY, USA.
authors.forename: Federico
authors.initials: F
authors.lastname: Giorgi
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY, USA.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Komissarova
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.affiliation: Department of Medicine, Division of Gastroenterology, Columbia University, New York, NY, USA.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
authors.forename: Antonia R
authors.initials: AR
authors.lastname: Sepulveda
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D014408:Biomarkers, Tumor / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D019295:Computational Biology; D018899:CpG Islands; D019175:DNA Methylation; D030541:Databases, Genetic; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005743:Gastrectomy; D005753:Gastric Mucosa / Q000737:chemistry* / Q000473:pathology / Q000601:surgery; D005756:Gastritis / Q000235:genetics / Q000473:pathology; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008679:Metaplasia; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D017422:Sequence Analysis, DNA / Q000379:methods*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery
chemical_list: D014408:Biomarkers, Tumor