Integrated Analysis of DNA Methylation and mRNA Expression Profiles Data to Identify Key Genes in Lung Adenocarcinoma

Introduction. Lung adenocarcinoma (LAC) is the most frequent type of lung cancer and has a high metastatic rate at an early stage. This study is aimed at identifying LAC-associated genes. Materials and Methods. GSE62950 downloaded from Gene Expression Omnibus included a DNA methylation dataset and an mRNA expression profiles dataset, both of which included 28 LAC tissue samples and 28 adjacent normal tissue samples. The differentially expressed genes (DEGs) were screened by Limma package in R, and their functions were predicted by enrichment analysis using TargetMine online tool. Then, protein-protein interaction (PPI) network was constructed using STRING and Cytoscape. Finally, LAC-associated methylation sites were identified by CpGassoc package in R and mapped to the DEGs to obtain LAC-associated DEGs. Results. Total 913 DEGs were identified in LAC tissues. In the PPI networks, MAD2L1, AURKB, CCNB2, CDC20, and WNT3A had higher degrees, and the first four genes might be involved in LAC through interaction. Total 8856 LAC-associated methylation sites were identified and mapped to the DEGs. And there were 29 LAC-associated methylation sites located in 27 DEGs (e.g., SH3GL2, BAI3, CDH13, JAM2, MT1A, LHX6, and IGFBP3). Conclusions. These key genes might play a role in pathogenesis of LAC.

[1]  Xuekun Song,et al.  CCNB2 overexpression is a poor prognostic biomarker in Chinese NSCLC patients. , 2015, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[2]  Hajime Saito,et al.  Strong expression of cyclin B2 mRNA correlates with a poor prognosis in patients with non-small cell lung cancer , 2014, Tumor Biology.

[3]  Yan-mei Yang,et al.  JAM-C promotes lymphangiogenesis and nodal metastasis in non-small cell lung cancer , 2014, Tumor Biology.

[4]  A. Nicholson,et al.  BAI3, CDX2 and VIL1: a panel of three antibodies to distinguish small cell from large cell neuroendocrine lung carcinomas , 2014, Histopathology.

[5]  F. Han,et al.  LHX6 acts as a novel potential tumour suppressor with epigenetic inactivation in lung cancer , 2013, Cell Death and Disease.

[6]  J. Hou,et al.  Long non-coding RNA metastasis associated in lung adenocarcinoma transcript 1 derived miniRNA as a novel plasma-based biomarker for diagnosing prostate cancer. , 2013, European journal of cancer.

[7]  N. Mukhopadhyay,et al.  SH3GL2 is frequently deleted in non-small cell lung cancer and downregulates tumor growth by modulating EGFR signaling , 2013, Journal of Molecular Medicine.

[8]  Gary D Bader,et al.  A travel guide to Cytoscape plugins , 2012, Nature Methods.

[9]  Tatsuya Kato,et al.  Overexpression of CDC20 predicts poor prognosis in primary non‐small cell lung cancer patients , 2012, Journal of surgical oncology.

[10]  Sébastien Couraud,et al.  Lung cancer in never smokers--a review. , 2012, European journal of cancer.

[11]  Richard T. Barfield,et al.  CpGassoc: an R function for analysis of DNA methylation microarray data , 2012, Bioinform..

[12]  Gang Feng,et al.  Disease Ontology: a backbone for disease semantic integration , 2011, Nucleic Acids Res..

[13]  Lokesh P. Tripathi,et al.  TargetMine, an Integrated Data Warehouse for Candidate Gene Prioritisation and Target Discovery , 2011, PloS one.

[14]  S. Chiou,et al.  Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation. , 2010, Cancer research.

[15]  Dennis B. Troup,et al.  NCBI GEO: archive for functional genomics data sets—10 years on , 2010, Nucleic Acids Res..

[16]  Randeep Rakwal,et al.  MALAT‐1 enhances cell motility of lung adenocarcinoma cells by influencing the expression of motility‐related genes , 2010, FEBS letters.

[17]  Y. Benjamini.  Discovering the false discovery rate , 2010 .

[18]  F. López-Ríos,et al.  IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-small-cell lung cancer , 2010, Oncogene.

[19]  Marc Ladanyi,et al.  WNT/TCF Signaling through LEF1 and HOXB9 Mediates Lung Adenocarcinoma Metastasis , 2009, Cell.

[20]  M. Nikiforova,et al.  Micropapillary lung adenocarcinoma: EGFR, K-ras, and BRAF mutational profile. , 2009, American journal of clinical pathology.

[21]  David Osumi-Sutherland,et al.  FlyBase: enhancing Drosophila Gene Ontology annotations , 2008, Nucleic Acids Res..

[22]  Pan Du,et al.  lumi: a pipeline for processing Illumina microarray , 2008, Bioinform..

[23]  Yusuke Nakamura,et al.  Phosphorylation and activation of cell division cycle associated 8 by aurora kinase B plays a significant role in human lung carcinogenesis. , 2007, Cancer research.

[24]  J. Sandbank,et al.  Usefulness of CDK5RAP3, CCNB2, and RAGE genes for the diagnosis of lung adenocarcinoma. , 2007, The International journal of biological markers.

[25]  Christian von Mering,et al.  STRING 7—recent developments in the integration and prediction of protein interactions , 2006, Nucleic Acids Res..

[26]  G. Giaccone,et al.  Frequent overexpression of aurora B kinase, a novel drug target, in non–small cell lung carcinoma patients , 2006, Molecular Cancer Therapeutics.

[27]  D. Amadori,et al.  p16INK4A and CDH13 hypermethylation in tumor and serum of non‐small cell lung cancer patients , 2006, Journal of cellular physiology.

[28]  M. Ueno,et al.  Wnt5a expression is associated with the tumor proliferation and the stromal vascular endothelial growth factor--an expression in non-small-cell lung cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  Y. Shim,et al.  Aberrant methylation of H‐cadherin (CDH13) promoter is associated with tumor progression in primary nonsmall cell lung carcinoma , 2005, Cancer.

[30]  R. Booton,et al.  Overexpression of aurora B kinase (AURKB) in primary non-small cell lung carcinoma is frequent, generally driven from one allele, and correlates with the level of genetic instability , 2005, British Journal of Cancer.

[31]  Martin Kuiper,et al.  BiNGO: a Cytoscape plugin to assess overrepresentation of Gene Ontology categories in Biological Networks , 2005, Bioinform..

[32]  Robert A. Winn,et al.  Restoration of Wnt-7a Expression Reverses Non-small Cell Lung Cancer Cellular Transformation through Frizzled-9-mediated Growth Inhibition and Promotion of Cell Differentiation* , 2005, Journal of Biological Chemistry.

[33]  Ronnie Driver,et al.  Biostatistics: a Methodology for the Health Sciences , 2005 .

[34]  Elisabeth Brambilla,et al.  Pathology and genetics of tumours of the lung , pleura, thymus and heart , 2004 .

[35]  Gary D. Bader,et al.  An automated method for finding molecular complexes in large protein interaction networks , 2003, BMC Bioinformatics.

[36]  M. Meyerson,et al.  Missense mutations of the BRAF gene in human lung adenocarcinoma. , 2002, Cancer research.

[37]  Pan‐Chyr Yang,et al.  Up-regulated caveolin-1 accentuates the metastasis capability of lung adenocarcinoma by inducing filopodia formation. , 2002, The American journal of pathology.

[38]  S. London,et al.  Insulin-like growth factor I, IGF-binding protein 3, and lung cancer risk in a prospective study of men in China. , 2002, Journal of the National Cancer Institute.

[39]  S. Theocharis,et al.  Expression of metallothionein in lung carcinoma: correlation with histological type and grade , 2002, Histopathology.

[40]  Diponkar Banerjee,et al.  Metallothionein expression in patients with small cell carcinoma of the lung , 2001, Cancer.

[41]  J. Minna,et al.  Loss of expression and aberrant methylation of the CDH13 (H-cadherin) gene in breast and lung carcinomas. , 2001, Cancer research.

[42]  Tobias Faust.  Pathology And Genetics Of Tumours Of The Lung Pleura Thymus And Heart , 2016 .

[43]  D. Stewart,et al.  Review Wnt Signaling Pathway in Non–small Cell Lung Cancer Overview of the Wnt Canonical (β-catenin) and Noncanonical Signaling Pathways , 2022 .

[44]  S. Kondo,et al.  Overexpression of MAD2 predicts clinical outcome in primary lung cancer patients. , 2011, Lung cancer.

[45]  Gábor Csárdi,et al.  The igraph software package for complex network research , 2006 .

[46]  Gordon K. Smyth,et al.  limma: Linear Models for Microarray Data , 2005 .

[47]  Hiroyuki Ogata,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 1999, Nucleic Acids Res..

[48]  H. Hansen,et al.  Lung cancer. , 1990, Cancer chemotherapy and biological response modifiers.

[49]  J. Higginson.  International Agency for Research on Cancer. , 1968, WHO chronicle.