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DNA hypomethylation-related overexpression of SFN, GORASP2 and ZYG11A is a novel prognostic biomarker for early stage lung adenocarcinoma.

ABSTRACT: Although alteration of DNA methylation in advanced cancer has been extensively investigated, few data for early-stage lung adenocarcinoma are available. Here, we compared DNA methylation profiles between adenocarcinoma in situ (AIS) and early invasive adenocarcinoma using the Infinium methylation array to investigate methylation abnormalities causing early progression of adenocarcinomas. We focused on differentially methylated sites which were located in promoter CpG islands or shore regions, and identified 579 hypermethylated sites and 23 hypomethylated sites in early invasive adenocarcinoma relative to AIS and normal lung. These hypermethylated genes were significantly associated with neuronal pathways such as the GABA receptor and serotonin signaling pathways. Among the hypomethylated genes, we found that GORASP2, ZYG11A, and SFN had significantly lower methylation rates at the shore regions and significantly higher protein expression in invasive adenocarcinoma. Moreover, overexpression of those proteins was strongly associated with patient's poor outcome. Despite DNA demethylation at the promoter region might be rare relative to DNA hypermethylation, we identified 2 new genes, GORASP2 and ZYG11A, which show hypomethylation and overexpression in invasive adenocarcinoma, suggesting that they have important functions in tumor cells. These genes may be clinically applicable as prognostic indicators and could be potential novel target molecules for drug development.

SUBMITTER: Husni RE

PROVIDER: S-EPMC6422190 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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DNA hypomethylation-related overexpression of SFN, GORASP2 and ZYG11A is a novel prognostic biomarker for early stage lung adenocarcinoma.

Husni Ryan Edbert RE Shiba-Ishii Aya A Nakagawa Tomoki T Dai Tomoko T Kim Yunjung Y Hong Jeongmin J Sakashita Shingo S Sakamoto Noriaki N Sato Yukio Y Noguchi Masayuki M

Oncotarget 20190226 17

Although alteration of DNA methylation in advanced cancer has been extensively investigated, few data for early-stage lung adenocarcinoma are available. Here, we compared DNA methylation profiles between adenocarcinoma <i>in situ</i> (AIS) and early invasive adenocarcinoma using the Infinium methylation array to investigate methylation abnormalities causing early progression of adenocarcinomas. We focused on differentially methylated sites which were located in promoter CpG islands or shore regi ...[more]

PMID: 30899432

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Project description:BackgroundThe incidence of stage I and stage II lung adenocarcinoma (LUAD) is likely to increase with the introduction of annual screening programs for high-risk individuals. We aimed to identify a reliable prognostic signature with immune-related genes that can predict prognosis and help making individualized management for patients with early-stage LUAD.MethodsThe public LUAD cohorts were obtained from the large-scale databases including 4 microarray data sets from the Gene Expression Omnibus (GEO) and 1 RNA-seq data set from The Cancer Genome Atlas (TCGA) LUAD cohort. Only early-stage patients with clinical information were included. Cox proportional hazards regression model was performed to identify the candidate prognostic genes in GSE30219, GSE31210 and GSE50081 (training set). The prognostic signature was developed using the overlapped prognostic genes based on a risk score method. Kaplan-Meier curve with log-rank test and time-dependent receiver operating characteristic (ROC) curve were used to evaluate the prognostic value and performance of this signature, respectively. Furthermore, the robustness of this prognostic signature was further validated in TCGA-LUAD and GSE72094 cohorts.ResultsA prognostic immune signature consisting of 21 immune-related genes was constructed using the training set. The prognostic signature significantly stratified patients into high- and low-risk groups in terms of overall survival (OS) in training data set, including GSE30219 (HR = 4.31, 95% CI 2.29-8.11; P = 6.16E-06), GSE31210 (HR = 11.91, 95% CI 4.15-34.19; P = 4.10E-06), GSE50081 (HR = 3.63, 95% CI 1.90-6.95; P = 9.95E-05), the combined data set (HR = 3.15, 95% CI 1.98-5.02; P = 1.26E-06) and the validation data set, including TCGA-LUAD (HR = 2.16, 95% CI 1.49-3.13; P = 4.54E-05) and GSE72094 (HR = 2.95, 95% CI 1.86-4.70; P = 4.79E-06). Multivariate cox regression analysis demonstrated that the 21-gene signature could serve as an independent prognostic factor for OS after adjusting for other clinical factors. ROC curves revealed that the immune signature achieved good performance in predicting OS for early-stage LUAD. Several biological processes, including regulation of immune effector process, were enriched in the immune signature. Moreover, the combination of the signature with tumor stage showed more precise classification for prognosis prediction and treatment design.ConclusionsOur study proposed a robust immune-related prognostic signature for estimating overall survival in early-stage LUAD, which may be contributed to make more accurate survival risk stratification and individualized clinical management for patients with early-stage LUAD.

Dataset Information

DNA hypomethylation-related overexpression of SFN, GORASP2 and ZYG11A is a novel prognostic biomarker for early stage lung adenocarcinoma.

Publications

DNA hypomethylation-related overexpression of SFN, GORASP2 and ZYG11A is a novel prognostic biomarker for early stage lung adenocarcinoma.

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