Abstract
BackgroundThe incidence of lung adenocarcinoma (LUAD) is increasing worldwide with different prognosis even in early-stage patients. We aimed to identify a prognostic panel with multiple DNA methylation biomarkers to predict survival in early-stage LUAD patients of different racial groups.MethodsThe methylation array, pyrosequencing methylation assay, Cox regression and Kaplan-Meier analyses were conducted to build the risk score equations of selected probes in a training cohort of 69 Asian LUAD patients. The risk score model was verified in another cohort of 299 Caucasian LUAD patients in The Cancer Genome Atlas (TCGA) database.ResultsWe performed a Cox regression analysis, in which the regression coefficients were obtained for eight probes corresponding to eight genes (AGTRL1, ALDH1A3, BDKRB1, CTSE, EFNA2, NFAM1, SEMA4A and TMEM129). The risk score was derived from sum of each methylated probes multiplied by its corresponding coefficient. Patients with the risk score greater than the median value showed poorer overall survival compared with other patients (p = 0.007). Such a risk score significantly predicted patients showing poor survival in TCGA cohort (p = 0.036). A multivariate analysis was further performed to demonstrate that the eight-probe panel association with poor outcome in early-stage LUAD patients remained significant even after adjusting for different clinical variables including staging parameters (hazard ratio, 2.03; p = 0.039).ConclusionsWe established a proof-of-concept prognostic panel consisting of eight-probe signature to predict survival of early-stage LUAD patients of Asian and Caucasian populations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-016-0276-x) contains supplementary material, which is available to authorized users.
Highlights
The incidence of lung adenocarcinoma (LUAD) is increasing worldwide with different prognosis even in early-stage patients
In the current study we focus on the development of survival predictors in early-stage LUAD patients by performing genome-wide methylation analysis and pyrosequencing quantitative methylation assay to select eight DNA methylation probes in a training cohort of 69 patients recruited in Taipei Veterans General Hospital (TVGH)
Marker discovery in genome-scale DNA methylation dataset In the marker selection phase of this study, we collected surgically dissected tumors of 69 early-stage LUAD patients from TVGH to form a training cohort for genome-wide methylation array analysis using Illumina Infinium HumanMethylation27 BeadChip
Summary
The incidence of lung adenocarcinoma (LUAD) is increasing worldwide with different prognosis even in early-stage patients. We aimed to identify a prognostic panel with multiple DNA methylation biomarkers to predict survival in early-stage LUAD patients of different racial groups. High-throughput methylation arrays are available to determine DNA methylation levels of thousands of CpG sites, simultaneously [7,8,9]. This technology enables large-scale DNA methylation analysis to identify informative DNA methylation biomarkers in lung cancer [7, 10,11,12,13,14,15,16]. The relevance of our finding has been validated in a cohort of 299 patients as part of The Cancer Genome Atlas (TCGA) project
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