title: Genes suppressed by DNA methylation in non-small cell lung cancer reveal the epigenetics of epithelial-mesenchymal transition.
abstract: BACKGROUND
  DNA methylation is associated with aberrant gene expression in cancer, and has been shown to correlate with therapeutic response and disease prognosis in some types of cancer. We sought to investigate the biological significance of DNA methylation in lung cancer.
  
  
  RESULTS
  We integrated the gene expression profiles and data of gene promoter methylation for a large panel of non-small cell lung cancer cell lines, and identified 578 candidate genes with expression levels that were inversely correlated to the degree of DNA methylation. We found these candidate genes to be differentially methylated in normal lung tissue versus non-small cell lung cancer tumors, and segregated by histologic and tumor subtypes. We used gene set enrichment analysis of the genes ranked by the degree of correlation between gene expression and DNA methylation to identify gene sets involved in cellular migration and metastasis. Our unsupervised hierarchical clustering of the candidate genes segregated cell lines according to the epithelial-to-mesenchymal transition phenotype. Genes related to the epithelial-to-mesenchymal transition, such as AXL, ESRP1, HoxB4, and SPINT1/2, were among the nearly 20% of the candidate genes that were differentially methylated between epithelial and mesenchymal cells. Greater numbers of genes were methylated in the mesenchymal cells and their expressions were upregulated by 5-azacytidine treatment. Methylation of the candidate genes was associated with erlotinib resistance in wild-type EGFR cell lines. The expression profiles of the candidate genes were associated with 8-week disease control in patients with wild-type EGFR who had unresectable non-small cell lung cancer treated with erlotinib, but not in patients treated with sorafenib.
  
  
  CONCLUSIONS
  Our results demonstrate that the underlying biology of genes regulated by DNA methylation may have predictive value in lung cancer that can be exploited therapeutically.
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd,, Unit 097, Houston, TX 77030, USA. shlin@mdanderson.org.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Lin
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Pierre
authors.initials: P
authors.lastname: Saintigny
authors.forename: Chia-Chin
authors.initials: CC
authors.lastname: Wu
authors.forename: Uma
authors.initials: U
authors.lastname: Giri
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Toshi
authors.initials: T
authors.lastname: Menju
authors.forename: Lixia
authors.initials: L
authors.lastname: Diao
authors.forename: Lauren
authors.initials: L
authors.lastname: Byers
authors.forename: John N
authors.initials: JN
authors.lastname: Weinstein
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Coombes
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Komaki
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Date
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D010641:Phenotype; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D015203:Reproducibility of Results
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride