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.

Association between <em>CHFR</em> gene hypermethylation and gastric cancer risk: a meta-analysis

“…In addition to studies from Asian populations, one study came from the Caucasian population. The results of this study showed that the CHFR methylation was significantly increased in gastric cancer compared with non-metaplastic mucosa 28. Taken together, these data showed a parallel effect of CHFR methylation on gastric cancer risk among different ethnicities.…”

Gastric Cancer in the Era of Precision Medicine

“…CIMP GCs tended to harbor mutations in the oncogenes CTNNB1 , ERBB2 , KRAS , and PIK3CA 74 . Similarly, reduced expression of hypermethylated BRINP1 , SGCE, and MLH1 was significantly associated with favorable survival in GC 75 . Moreover, infectious agents such as H pylori , EBV, and the infection-associated inflammatory response all induce altered DNA methylation 76, 77, 78.…”

Early detection of gastric cancer using global, genome-wide and IRF4, ELMO1, CLIP4 and MSC DNA methylation in endoscopic biopsies

“…The literature reports many genes significantly hypermethylated in cancer tissue compared with normal tissue of GC subjects [18–20], but relatively few studies have reported DNA methylation markers for early detection [21–24]. Furthermore, quantification of global 5-methylcytosine content [25] and evaluation of long interspersed nuclear elements (LINEs) by Lee [26] and others have emphasized the importance of global DNA hypomethylation in GCs, although little is known about its role in GC.…”