Genes suppressed by DNA methylation in non-small cell lung cancer reveal the epigenetics of epithelial–mesenchymal transition

BMC Genomics

John V Heymach²  John D Minna⁹  Hiroshi Date¹  Ignacio I Wistuba⁵  Ritsuko Komaki⁷  Luc Girard⁹  Kevin R Coombes⁴  John N Weinstein⁶  Lauren Byers²  Lixia Diao⁷  Toshi Menju²  Jing Zhang⁷  Uma Giri²  Chia-Chin Wu⁸  Pierre Saintigny³  Jing Wang⁶  Steven H Lin⁷ 

[1] Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan;Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 097, Houston, TX 77030, USA;Cancer Research Center of Lyon, UMR INSERM 1052 / CNRS 5286 Mixte CLB, Centre Léon Bérard, 28 rue Laennec, 69373 Lyon, Cedex 08, France;Ohio State University College of Medicine, 250 Lincoln Tower, 1800 Cannon Drive, Columbus, Ohio, USA;Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA;Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 097, Houston, TX 77030, USA;Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 097, Houston, TX 77030, USA;Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA;Hamon Center for Therapeutic Oncology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA

关键词: Lung cancer;    Erlotinib;    Epithelial-mesenchymal transition;    DNA methylation;   

Others  :  1127475
DOI  :  10.1186/1471-2164-15-1079

 received in 2014-07-04, accepted in 2014-11-26,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Lin et al.; licensee BioMed Central Ltd.

【 图 表 】

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