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Epigenetic analysis of microRNA genes in tumors from surgically resected lung cancer patients and association with survival.

ABSTRACT: Aberrant microRNA (miRNA) expression is involved in tumorigenesis of several cancers, including non-small cell lung cancer (NSCLC). Furthermore, expression of some miRNAs has been shown to be under epigenetic regulation. However, less is known regarding the role of miRNA methylation in NSCLC development or clinical outcomes. Therefore, we tested miRNA methylation patterns by quantitative real-time methylation-specific PCR for a panel of candidate miRNAs in 19 NSCLC paired tumor and adjacent normal tissues. For assessment of survival, methylation was measured in a total of 97 tumor tissues with complete clinical and follow-up data. Analysis was also performed for correlation with age at diagnosis, gender, smoking, and stage. Significant differences in methylation patterns were observed for 9 of the 12 miRNAs, all due to hypermethylation in the tumor tissue. Individuals with the highest levels of methylated miR-127 were at a significantly increased risk of dying with a hazard ratio of 1.93 (95% CI 1.17-3.19; P?=?0.010), in univariate analysis and remained significant after adjusting for age, gender, and stage (HR 1.97; 95% CI 1.15-3.40; P?=?0.014). This increase in risk due to increased methylation were accompanied by significant, dramatic difference in survival duration of 17 months (P?=?0.0089). Six of the 12 miRNAs were significantly positively correlated with age at diagnosis. Additionally, methylation of miR-127 was significantly greater in higher stage tumors compared to lower stage tumors (P?=?0.0039). However, no significant associations between smoking and gender with miRNA methylation were observed. Our results demonstrate that miRNA methylation plays a role in NSCLC tumorigenesis and prognosis.

SUBMITTER: Tan W

PROVIDER: S-EPMC4814160 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Epigenetic analysis of microRNA genes in tumors from surgically resected lung cancer patients and association with survival.

Tan Weiqi W Gu Jian J Huang Maosheng M Wu Xifeng X Hildebrandt Michelle A T MA

Molecular carcinogenesis 20140324

Aberrant microRNA (miRNA) expression is involved in tumorigenesis of several cancers, including non-small cell lung cancer (NSCLC). Furthermore, expression of some miRNAs has been shown to be under epigenetic regulation. However, less is known regarding the role of miRNA methylation in NSCLC development or clinical outcomes. Therefore, we tested miRNA methylation patterns by quantitative real-time methylation-specific PCR for a panel of candidate miRNAs in 19 NSCLC paired tumor and adjacent norm ...[more]

PMID: 24665010

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Project description:Background: Lung cancer has the highest morbidity and mortality of cancers worldwide. Lung adenocarcinoma (LUAD) is the most common pathological subtype of lung cancer and surgery is its most common treatment. The dysregulated expression of DNA repair genes is found in a variety of cancers and has been shown to affect the origin and progression of these diseases. However, the function of DNA repair genes in surgically-treated LUAD is unclear.Methods: We sought to determine the association between the signature of DNA repair genes for patients with surgical LUAD and their overall prognosis. We obtained gene expression data and corresponding clinical information of LUAD from The Cancer Genome Atlas (TCGA) database. The differently expressed DNA repair genes of surgically-treated LUAD and normal tissues were identified using the Wilcoxon rank-sum test. We used uni- and multivariate Cox regression analyses to shrink the aberrantly expressed genes, which were then used to construct the prognostic signature and the risk score formula associated with the independent prognosis of surgically-treated LUAD. We used Kaplan-Meier and Cox hazard ratio analyses to confirm the diagnostic and prognostic roles. Two validation sets (GSE31210 and GSE37745) were downloaded from the Gene Expression Omnibus (GEO) and were used to externally verify the prognostic value of the signature. OSluca online database verifies the hazard ratio for the DNA repair genes by which the signature was constructed. We investigated the correlation between the signature of the DNA repair genes and the clinical parameters. The potential molecular mechanisms and pathways of the prognostic signature were explored using Gene Set Enrichment Analysis (GSEA).Results: We determined the prognostic signature based on six DNA repair genes (PLK1, FOXM1, PTTG1, CCNO, HIST3H2A, and BLM) and calculated the risk score based on this formula. Patients with surgically-treated LUAD were divided into high-risk and low-risk groups according to the median risk score. The high-risk group showed poorer overall survival than the low-risk group; the signature was used as an independent prognostic indicator and had a greater prognostic value in surgically-treated LUAD. The prognostic value was replicated in GSE31210 and GSE37745. OSluca online database analysis shows that six DNA repair genes were associated with poor prognosis in most lung cancer datasets. The prognostic signature risk score correlated with the pathological stage and smoking status in surgically-treated LUAD. The GSEA of the risk signature in high-risk patients showed pathways associated with the cell cycle, oocyte meiosis, mismatch repair, homologous recombination, and nucleotide excision repair.Conclusions: A six-DNA repair gene signature was determined using TCGA data mining and GEO data verification. The gene signature may serve as a novel prognostic biomarker and therapeutic target for surgically-treated LUAD.

Dataset Information

Epigenetic analysis of microRNA genes in tumors from surgically resected lung cancer patients and association with survival.

Publications

Epigenetic analysis of microRNA genes in tumors from surgically resected lung cancer patients and association with survival.

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