Dataset Information

Aberrant methylation of microRNA-34b/c is a predictive marker of metachronous gastric cancer risk.

ABSTRACT:

Background

Metachronous gastric cancer (GC) can develop after endoscopic resection of GC and cannot be predicted based on clinical signature. Aberrant DNA methylation in noncancerous gastric mucosa is strongly implicated in gastric carcinogenesis and could be a useful biomarker of GC risk. We evaluated the clinical utility of DNA methylation as a biomarker of metachronous GC risk.

Method

We carried out scheduled follow-up endoscopy in 129 patients after curative endoscopic resection of GC. Biopsy specimens were collected from noncancerous mucosa in the gastric antrum and body, after which quantitative methylation analysis of miR-34b/c, SFRP1, SFRP2, SFRP5, DKK2 and DKK3 was carried out using bisulfite pyrosequencing. The utility of the methylation for predicting the risk of metachronous GC development was assessed using Kaplan-Meier and Cox proportional hazards model analyses.

Results

During the follow-up period, 17 patients (13%) developed metachronous GCs. The cumulative incidence of metachronous GC was significantly higher among patients with elevated miR-34b/c, SFRP2 and DKK2 methylation in their gastric body. MiR-34b/c showed the strongest association with the risk of metachronous GC, and the cumulative incidence of metachronous GC was much higher in the high-miR-34b/c-methylation group than the low-methylation group. Multivariate analysis adjusted for age, sex, H. pylori status and pathological findings showed miR-34b/c methylation in gastric body to be an independent predictor of metachronous GC risk.

Conclusion

Our results suggest that methylation of miR-34b/c in the mucosa of the noncancerous gastric body may be a useful biomarker for predicting the risk of metachronous GC.

SUBMITTER: Suzuki R

PROVIDER: S-EPMC4083150 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Background: The prognosis of gastric cancer (GC) patients is poor. The effect of aberrant DNA methylation on FOXF2 expression and the prognostic role of FOXF2 methylation in GC have not yet been identified. Methods: The RNA-Seq and gene methylation HM450 profile data were used for analyzing FOXF2 expression in GC and its association with methylation level. Bisulfite sequencing PCR (BSP) was performed to measure the methylation level of the FOXF2 promoter region in GC cell lines and normal GES-1 cells. The cells were treated with the demethylation reagent 5-Aza-dC, and the mRNA and protein expression levels of FOXF2 were then measured by qRT-PCR and western blot assays. The risk score system from SurvivalMeth was calculated by integrating the methylation level of the cg locus and the corresponding Cox regression coefficient. Results: FOXF2 was significantly downregulated in GC cells and tissues. On the basis of RNA-Seq and Illumina methylation 450 data, FOXF2 expression was significantly negatively correlated with the FOXF2 methylation level (Pearson's R = -0.42, p < 2.2e-16). The FOXF2 methylation level in the high FOXF2 expression group was lower than that in the low FOXF2 expression group. The BSP assay indicated that the methylation level of the FOXF2 promoter region in GC cell lines was higher than that in GES-1 cells. The qRT-PCR and western blot assay showed that FOXF2 mRNA and protein levels were increased in GC cells following treatment with 5-Aza-Dc. The methylation risk score model indicated that patients in the high risk group had poorer survival probability than those in the low risk group (HR = 1.84 (1.11-3.07) and p = 0.0068). FOXF2 also had a close transcriptional regulation network with four miRNAs and their corresponding target genes. Functional enrichment analysis of the target genes revealed that these genes were significantly related to several important signaling pathways. Conclusion: FOXF2 was downregulated due to aberrant DNA methylation in GC, and the degree of methylation in the promoter region of FOXF2 was related to the prognosis of patients. The FOXF2/miRNAs/target genes axis may play a vital biological regulation role in GC.

Project description:BackgroundOvarian metastasis following radical gastrectomy, also known as metachronous ovarian metastasis (MOM), pose a significant threat to the long-term survival of female gastric cancer (GC) patients. However, a mechanism to identify and characterize operated patients at high risk of developing MOM remains unknown. This retrospective study aimed to identify risk factors for the occurrence of MOM based on the profiling of clinicopathological parameters and expression of sex hormone receptors (SHR) of operated GC patients with and without ovarian relapse.MethodsThe clinicopathological data of 1,055 female GC patients from two medical centers who underwent surgery between January 2011 and December 2015 were reviewed. A total of 378 patients with and without the occurrence of MOM met the eligibility criteria, including the availability of medical records, adequacy of lymph node dissection, completeness of clinicopathological data, sufficient follow-up time, and no administration of neoadjuvant chemotherapy were selected for further analysis. Expressions of estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and progesterone receptor (PR) were detected by immunohistochemical staining on the surgical specimens of patients, and retrospective statistical analyses identified independent risk factors for the occurrence of MOM. A risk prediction model in the format of a polygenic hazard score (PHS) for the occurrence of MOM was established by introducing and modifying the previously validated polygenic risk score (PRS)/PHS.ResultsA Cox regression-based multivariate analysis identified premenopausal with an HR of 3.15 (95% CI, 1.66-5.98), more advanced pathological T stage with an HR of 3.79 (95% CI, 2.14-6.69), more advanced pathological N stage with an HR of 1.85 (95% CI, 1.35-2.54), and negative expression of ERβ with an HR of 0.33 (95% CI, 0.15-0.7) as independent risk factors for the occurrence of MOM (P<0.01). Accordingly, a PHS for the occurrence of MOM was established, with 1-, 2-, and 3-year ovarian relapse rates for the high-risk group estimated at 17.8%, 33.7%, and 46.2%, respectively.ConclusionsPremenopausal status, depth of tumor invasion, number of positive lymph nodes, and negative expression of ERβ were independent factors for the occurrence of MOM. More frequent follow-up examinations are recommended to provide timely diagnosis and medical intervention.