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Accumulated promoter methylation as a potential biomarker for esophageal cancer.

ABSTRACT: We performed a two-stage molecular epidemiological study to explore DNA methylation profiles for potential biomarkers of esophageal squamous cell carcinoma (ESCC) in a Chinese population. Infinium Methylation 450K BeadChip was used to identify genes with differentially methylated CpG sites. Sixteen candidate genes were validated by sequencing 1160 CpG sites in their promoter regions using the Illumina MiSeq platform. When excluding sites with negative changes, 10 genes (BNIP3, BRCA1, CCND1, CDKN2A, HTATIP2, ITGAV, NFKB1, PIK3R1, PRDM16 and PTX3) showed significantly different methylation levels among cancer lesions, remote normal-appearing tissues, and healthy controls. PRDM16 had the highest diagnostic value with the AUC (95% CI) of 0.988 (0.965-1.000), followed by PIK3R1, with the AUC (95% CI) of 0.969 (0.928-1.000). In addition, the methylation status was higher in patients with advanced cancer stages. These results indicate that aberrant DNA methylation may be a potential biomarker for the diagnosis of ESCC.

SUBMITTER: Peng X

PROVIDER: S-EPMC5352188 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Accumulated promoter methylation as a potential biomarker for esophageal cancer.

Peng Xianzhen X Xue Hengchuan H Lü Lingshuang L Shi Peiyi P Wang Jianping J Wang Jianming J

Oncotarget 20170101 1

We performed a two-stage molecular epidemiological study to explore DNA methylation profiles for potential biomarkers of esophageal squamous cell carcinoma (ESCC) in a Chinese population. Infinium Methylation 450K BeadChip was used to identify genes with differentially methylated CpG sites. Sixteen candidate genes were validated by sequencing 1160 CpG sites in their promoter regions using the Illumina MiSeq platform. When excluding sites with negative changes, 10 genes (BNIP3, BRCA1, CCND1, CDKN ...[more]

PMID: 27893424

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Project description:BACKGROUND:Cervical cancer screening by combined cytology and HPV test has reduced the incidence of cervical cancer, but cytological screening lacks a higher sensitivity while HPV testing possesses a lower specificity. Most patients with invasive cervical cancer are treated with radiotherapy. However, insensitivity to radiotherapy leads to poor efficacy. METHODS:Illumina Methylation EPIC 850k Beadchip was used for genomic screening. We detected methylation of SEPT9 and mRNA expression in different cervical tissues by using methylation-specific PCR and qRT-PCR. Then using CCK8, migration assay, and flow cytometry to detect the biological function and irradiation resistance of SEPT9 in vitro and in vivo. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and co-immunoprecipitation (CoIP) were used to find the interacting gene with SEPT9. Immunostaining of CD206 in cervical cancer and polarization of macrophages (M2) were evaluated by immunofluorescence and WB. The Cancer Genome Atlas (TCGA) database was used for screening the potential miRNAs induced by SEPT9. RESULTS:Hyper-methylation of SEPT9 detects cervical cancer and normal tissues, normal+CIN1 and CIN2+CIN3+cancer with high sensitivity and specificity (AUC = 0.854 and 0.797, respectively, P < 0.001). The mRNA and protein expression of SEPT9 was upregulated in cervical cancer tissues when compared to para-carcinoma tissues. SEPT9 promotes proliferation, invasion, migration, and influences the cell cycle of cervical cancer. SEPT9 interacted with HMGB1-RB axis increases irradiation resistance. Furthermore, SEPT9 mediated miR-375 via the tumor-associated macrophages (TAMs) polarization, affecting the resistance to radiotherapy in cervical cancer. CONCLUSIONS:These findings give us the evidence that SEPT9 methylation could be a biomarker for cervical cancer diagnoses. It promotes tumorigenesis and radioresistance of cervical cancer by targeting HMGB1-RB axis and causes polarization of macrophages by mediating miR-375. We suggest SEPT9 could be a potential screening and therapeutic biomarker for cervical cancer.

Project description:BackgroundRunt-related transcription factor 3 (RUNX3) is a member of the runt-domain family of transcription factors. Emerging evidence indicates that RUNX3 is a tumor suppressor gene in several types of human cancers including esophageal cancer. However, the association between RUNX3 promoter methylation and esophageal cancer remains unclear. Here we conducted a systematic review and meta-analysis to quantitatively evaluate the effects of RUNX3 promoter methylation on the incidence of esophageal cancer.MethodsA detailed literature search was made on Medline, Pubmed and Web of Science for related research publications written in English and/or Chinese. Methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analysis of pooled data were performed, the odds ratios (OR) were calculated and summarized respectively.ResultsFinal analysis of 558 patients from 9 eligible studies was performed. The result showed that RUNX3 methylation was significantly higher in esophageal cancer than in normal squamous mucosa from the proximal resection margin or esophageal benign lesions (OR = 2.85, CI = 2.01-4.05, P<0.00001). The prevalence of lymph node involvement, tumor size (T1-T2 vs T3-T4) and histological grade was significantly greater in RUNX3-negative cases (RUNX3 unmethylated groups) than in RUNX3-positive cases (OR = 0.25, CI = 0.14-0.43, P<0.00001). RUNX3 methylation was significantly higher in esophageal adenocarcinoma (EAC) than Barrett's esophagus (OR = 0.35, CI = 0.20-0.59, P<0.0001). In addition, the pooled HR for overall survival (OS) showed that decreased RUNX3 expression was associated with worse survival in esophageal cancer (HR = 4.31, 95% CI = 2.57-7.37, P<0.00001).ConclusionsThe results of this meta-analysis suggest that RUNX3 methylation is associated with an increased risk, progression as well as worse survival in esophageal cancer. RUNX3 methylation, which induces the inactivation of RUNX3 gene, plays an important role in esophageal carcinogenesis.

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Accumulated promoter methylation as a potential biomarker for esophageal cancer.

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Accumulated promoter methylation as a potential biomarker for esophageal cancer.

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