Aberrant methylation‐mediated downregulation of long noncoding RNA C5orf66‐AS1 promotes the development of gastric cardia adenocarcinoma

Guo, Wei; Lv, Ping; Liu, Shengnan; Xu, Fenglou; Guo, Yanli; Shen, Supeng; Liang, Jia; Kuang, Gang; Zhang, Dong

doi:10.1002/mc.22806

Cited by 26 publications

(21 citation statements)

References 32 publications

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“…Recent studies have showed that expression alterations of lncRNA-encoding genes mediated by changes in methylation can subsequently affect their downstream targets. For instance, the lncRNA C5orf66-AS1 functions as a tumor suppressor gene in GC, and aberrant hypermethylation of the regions around its transcription start site (TSS) is associated with its expression and is cancer-specific (Guo et al, 2018). This study indicated that hypermethylation of the C5orf66-AS1 promoter may serve as a potential prognostic marker in predicting GC patient survival.…”

Section: Introductionmentioning

confidence: 94%

“…DNA methylation, a key epigenetic mechanism, plays a crucial role in the regulation of gene expression, genomic imprinting, genome stabilization, and chromatin modification. Aberrant DNA methylation has been reported to be involved in the formation and progressions of diseases, especially cancers (Guo et al, 2018;Xu et al, 2019). Recent studies have showed that expression alterations of lncRNA-encoding genes mediated by changes in methylation can subsequently affect their downstream targets.…”

Section: Introductionmentioning

confidence: 99%

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Genome-Wide Identification and Characterization of DNA Methylation and Long Non-Coding RNA Expression in Gastric Cancer

Song

Guan

2020

Front. Genet.

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Abnormal DNA methylation, an epigenetic modification, has increasingly been linked to the pathogenesis of many human cancers. However, there has been little focus on the DNA methylation patterns of genes encoding long noncoding RNAs (lncRNAs) in gastric cancer (GC). This study comprehensively determined DNA methylation and lncRNA expression profiles in GC through genome-wide analysis. Differentially methylated loci and lncRNAs were identified by integrating multi-omics data. In total, 548 differentially methylated CpG sites in lncRNA promoters and 2,399 differentially expressed lncRNAs were screened that were capable of distinguishing GC from normal tissues. Among them, 22 differentially methylation sites in 17 lncRNAs were inversely related to expression levels. Further analysis of DNA methylation status and gene expression level in GC revealed that three CpG sites (cg01550148, cg22497867, and cg20001829) and two lncRNAs (RP11-366F6.2 and RP5-881L22.5) were significantly associated with GC patient overall survival. Molecular function analysis showed that these abnormally methylated lncRNAs were mainly involved in transcriptional activator activity. Our study identified several lncRNAs regulated by aberrant DNA methylation that have clinical utility as novel prognostic biomarkers in GC. These findings help improve the understanding of methylated patterns of lncRNAs and further our knowledge of the role of epigenetics in cancer development.

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Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Genome-Wide Identification and Characterization of DNA Methylation and Long Non-Coding RNA Expression in Gastric Cancer

Song

Guan

2020

Front. Genet.

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“…LincRNA C5orf66-AS1 hypomethylation was significantly associated with overall survival in patients with the squamous cell cancer in the head and neck region [27]. The aberrant hypermethylation-mediated downregulation of C5orf66-AS1 might play an important role in gastric cardia adenocarcinoma tumorigenesis and might serve as a potential prognostic biomarker in predicting gastric cardia adenocarcinoma patients' survival [28].…”

Section: Discussionmentioning

confidence: 96%

Integrated analysis reveals potential long non-coding RNA biomarkers and their potential biological functions for disease free survival in gastric cancer patients

et al. 2019

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Background Increasing evidences supported the association between long non-coding RNA (lncRNA) and disease free survival in gastric cancer (GC) patients. The purpose of the current study was to construct and verify a noninvasive preoperative predictive tool for disease free survival in GC patients. Methods There were 265 and 300 GC patients in model dataset and validation dataset respectively. The associations between the lncRNA biomarkers and disease free survival were evaluated by univariate and multivariate Cox regression. Results Thirteen lncRNA biomarkers (GAS5-AS1, AL109615.3, KDM7A-DT, AP000866.2, KCNJ2-AS1, LINC00656, LINC01777, AC046185.3, TTTY14, LINC01526, LINC02523, LINC00592, and C5orf66) were identified as prognostic biomarkers with disease free survival. These thirteen lncRNA biomarkers were combined to construct a prognostic signature for disease free survival. The C-indexes of the current predictive signature in model cohort were 0.849 (95% CI 0.803–0.895), 0.859 (95% CI 0.813–0.905) and 0.888 (95% CI 0.842–0.934) for 1-year, 3-year and 5-year disease free survival respectively. Based on thirteen-lncRNA prognostic signature, patients in model cohort could be stratified into high risk group and low risk group with significant different disease free survival rate (hazard ratio [HR] = 7.355, 95% confidence interval [CI] 4.378–12.356). Good reproducibility of thirteen-lncRNA prognostic signature was confirmed in an external validation cohort (GSE62254) with HR 3.919 and 95% CI 2.817–5.453. Further analysis demonstrated that the prognostic significance of thirteen-lncRNA prognostic signature was independent of other clinical characteristics. Conclusions In conclusion, a simple noninvasive prognostic signature was established for preoperative prediction of disease free survival in GC patients. This prognostic signature might predict the individual mortality risk of disease free survival without pathological information and facilitate individual treatment decision-making. Electronic supplementary material The online version of this article (10.1186/s12935-019-0846-6) contains supplementary material, which is available to authorized users.

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“…Also, the enhancer region and proximal promoter hypermethylation and dysregulation of MEG3 and miR‐770 were correlated with a survival of poorer CGA patients . Aberrant hypermethylation‐mediated downregulation of C5orf66‐AS1 may play critical roles in CGA tumorigenesis and C5orf66‐AS1 can be a prognostic marker in the prediction of CGA patients' survival . Epigenetic silencing of Wnt‐antagonist gene expression via promoter hypermethylation can influence CGA …”

Section: Epigenetic Risk Factorsmentioning

confidence: 98%

Risk factors predisposing to cardia gastric adenocarcinoma: Insights and new perspectives

et al. 2019

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Recent decades have seen an alarming increase in the incidence of cardia gastric adenocarcinoma (CGA) while noncardia gastric adenocarcinoma (NCGA) has decreased. In 2012, 260 000 CGA cases (age‐standardised rate (ASR); 3.3/100 000) and 691 000 NCGA cases (ASR; 8.8/100 000) were reported worldwide. Compared with women, men had greater rates for both the subsites, especially for CGA. Recently, four molecular subtypes of GC have been proposed by the Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG); however, these classifications do not take into account predisposing germline variants and their possible interaction with somatic alterations in carcinogenesis. The etiology of adenocarcinoma of the cardia and the gastroesophageal junction (GEJ) is not known. It is thought that CGA is distinct from adenocarcinomas located in the esophagus or distal stomach, both epidemiologically and biologically. Moreover, CGA is often identified in the advanced stage having a poor prognosis. Therefore, understanding the risk and the role of predisposing factors in etiology of CGA can inform clinical practice and counseling for risk reduction. In this paper, we showed that GC family history, lifestyle, demographics, gastroesophageal reflux disease, Helicobacter pylori infection, and multiple genetic and epigenetic risk factors as well as several predisposing conditions may underlie susceptibility to CGA. However, several genome‐wide association studies (GWASs) should be conducted to identify novel high‐penetrance genes and pathways as well as causal germline variants predisposing to CGA. They must include different ethnic groups, especially from high‐incidence countries for CGA, because some risk loci are ancestry‐specific. In parallel, statistical methods can be developed to identify cancer predisposition genes (CPGs) from tumor sequencing data. It is also necessary to find novel long noncoding RNAs related to the risk of CGA. Taken altogether, new cancer risk prediction models, including all genetic and nongenetic factors influencing risk, should be developed to facilitate risk assessment, disease prevention, and early diagnosis and intervention of CGA in the future.

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Aberrant methylation‐mediated downregulation of long noncoding RNA C5orf66‐AS1 promotes the development of gastric cardia adenocarcinoma

Cited by 26 publications

References 32 publications

Genome-Wide Identification and Characterization of DNA Methylation and Long Non-Coding RNA Expression in Gastric Cancer

Genome-Wide Identification and Characterization of DNA Methylation and Long Non-Coding RNA Expression in Gastric Cancer

Integrated analysis reveals potential long non-coding RNA biomarkers and their potential biological functions for disease free survival in gastric cancer patients

Risk factors predisposing to cardia gastric adenocarcinoma: Insights and new perspectives

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