Abstract：Objective To identify prognostic biomarkers for ESCC patients in order to ensure good outcomes.Methods The DNA methylation profile data on 96 ESCC tissues and 3 normal tissues was downloaded from the Cancer Genome Atlas Database (TCGA). Cox proportional hazards regression and random survival forest-variable hunting were used to identify DNA methylated gene biomarkers in the samples that were randomly assigned to the training group, with other samples as the test subset. GO annotation was performed to explore the biological function of DNA methylated gene signatures.Results A total of 283 different methylation genes were identified in the ESCC data. Finally, 4 methylation genes (RRAGB, SYP, ERCC6L and RNASEH2CP1) that were significantly associated with patients’ survival time were identified as biomarkers. As the most accurate predictor, the area under the curve (AUC) in the training and test groups was 0.984 and 0.83, respectively. The signature was able to sort patients into high- and low-risk groups with meaningful survival rates in the training group, and its predictive ability was validated in the test dataset. Multivariable Cox regression analysis showed the methylation gene biomarker was an independent prognostic factor for ESCC patients. Functional analysis suggested that these signature genes might be related to the regulation of transcription and DNA binding.Conclusions DNA methylation gene signatures could be novel prognostic biomarkers and can help predict the survival of ESCC patients independently.
Zhang Y. Epidemiology of esophageal cancer[J]. World J Gastroenterol, 2013, 19(34):5598-5606.
[2]
Pennathur A, Gibson M K, Jobe B A, et al. Oesophageal carcinoma[J]. Lancet, 2013, 381(9864):400-412.
[3]
Ferlay J, Shin H R, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008[J]. Int J Cancer, 2010, 127(12):2893-2917.
[4]
Domper Arnal M J, Ferrandez A A, Lanas A A. Esophageal cancer: risk factors, screening and endoscopic treatment in western and eastern countries[J]. World J Gastroenterol, 2015, 21(26):7933-7943.
[5]
Guo H, Zhu P, Yan L, et al. The DNA methylation landscape of human early embryos[J]. Nature,2014, 511(7511):606-610.
[6]
Robertson K D. DNA methylation and human disease[J]. Nat Rev Genet, 2005, 6(8):597-610.
[7]
Xu X. DNA methylation and cognitive aging[J]. Oncotarget, 2015, 6(16):13922-13932.
[8]
Brock M V, Hooker C M, Ota-Machida E, et al. DNA methylation markers and early recurrence in stage I lung cancer[J]. N Engl J Med, 2008, 358(11):1118-1128.
[9]
Ambrosone C B, Young A C, Sucheston L E, et al. Genome-wide methylation patterns provide insight into differences in breast tumor biology between American women of African and European ancestry[J]. Oncotarget, 2014, 5(1):237-48.
[10]
Gaedcke J, Leha A, Claus R, et al. Identification of a DNA methylation signature to predict disease-free survival in locally advanced rectal cancer[J]. Oncotarget, 2014, 5(18):8123-8135.
[11]
Fukuoka T, Hibi K, Nakao A. Aberrant methylation is frequently observed in advanced esophageal squamous cell carcinoma[J]. Anticancer Res, 2006, 26(5A):3333-3335.
[12]
Guo M, Ren J, House M G, et al. Accumulation of promoter methylation suggests epigenetic progression in squamous cell carcinoma of the esophagus[J]. Clin Cancer Res, 2006, 12(15):4515-4522.
[13]
Liu J B, Qiang F L, Dong J, et al. Plasma DNA methylation of Wnt antagonists predicts recurrence of esophageal squamous cell carcinoma[J]. World J Gastroenterol, 2011, 17(44):4917-4921.
[14]
Enzinger P C, Mayer R J. Esophageal cancer[J]. N Engl J Med,2003, 349(23):2241.
[15]
Gao C, Zhuang J, Zhou C, et al. Prognostic value of aberrantly expressed methylation gene profiles in lung squamous cell carcinoma: a study based on the cancer genome atlas[J].J Cell Physiol,2018, 234(5):6519-6528.
[16]
Fan G, Tu Y, Chen C, et al. DNA methylation biomarkers for hepatocellular carcinoma[J]. Cancer Cell Int, 2018, 18:140.
[17]
Chen Z Y, Zhang J L, Yao H X, et al. Aberrant methylation of the SPARC gene promoter and its clinical implication in gastric cancer[J]. Sci Rep, 2014, 4:7035.
[18]
Dinardo C D, Luskin M R, Carroll M, et al. Validation of a clinical assay of multi‐locus DNA methylation for prognosis of newly diagnosed AML[J]. Am J Hematol, 2016, 92(2): E14-E15.
[19]
Ganji S M, Miotto E, Callegari E, et al. Associations of risk factors obesity and occupational airborne exposures with CDKN2A/p16 aberrant DNA methylation in esophageal cancer patients[J]. Dis Esophagus, 2010, 23(7):597-602.
[20]
Liang W, Herman J G, Brock M V, et al. Silencing DACH1 promotes esophageal cancer growth by inhibiting TGF-β signaling[J]. PLoS One, 2014, 9(4):e95509.
[21]
Cheng Y, Geng H, Cheng S H, et al. KRAB Zinc finger protein ZNF382 is a proapoptotic tumor suppressor that represses multiple oncogenes and is commonly silenced in multiple carcinomas[J]. Cancer Res, 2010, 70(16):6516-6526.
[22]
Lee E J, Lee B B, Kim J W, et al. Aberrant methylation of fragile histidine triad gene is associated with poor prognosis in early stage esophageal squamous cell carcinoma[J]. Eur J Cancer, 2006, 42(7):0-980.
[23]
Sekiguchi T, Furuno N, Ishii T, et al. RagA, an mTORC1 activator, interacts with a hedgehog signaling protein, WDR35/IFT121[J]. Genes Cells, 2019, 24(2):151-61.
[24]
Li Y, Zhang Q, Lovnicki J, et al. SRRM4 gene expression correlates with neuroendocrine prostate cancer[J]. Prostate, 2019, 79(1):96-104.
[25]
Liu J, Sun J, Zhang Q, et al. shRNA knockdown of DNA helicase ERCC6L expression inhibits human breast cancer growth[J]. J Vis Exp, 2017, 2017(123): 3490-3496.
2020, Vol. 31 
