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

Steven Lin 1, * Jing Wang 2, * Pierre Saintigny 3 Chia-Chin Wu 4 Uma Giri 5 Jing Zhang 1 Toshi Menju 5 Lixia Diao 1 Lauren Byers 5 John Weinstein 2 Kevin Coombes 6 Luc Girard 7 Ritsuko Komaki 1 Ignacio Wistuba 8 Hiroshi Date 9 John Minna 7 John Heymach 5, *
* Auteur correspondant
1 Department of Radiation Oncology
2 Department of Bioinformatics and Computational Biology
3 CRCL - Centre de Recherche en Cancérologie de Lyon
4 Department of Genomic Medecine
5 Department of Thoracic/Head and Neck Medical Oncology
6 Ohio State University College of Medicine
7 Hamon Center for Therapeutic Oncology
8 Department of Pathology
9 Department of Thoracic Surgery
Abstract : 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. 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. 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.
Keywords : Epithelia l-mesenchymal transitio n DNA methylation Erlotinib Lung cancer
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BMC Genomics, BioMed Central, 2013, 15, pp.1079
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Soumis le : mardi 3 mars 2015 - 17:20:34
Dernière modification le : vendredi 23 mars 2018 - 16:43:00

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Steven Lin, Jing Wang, Pierre Saintigny, Chia-Chin Wu, Uma Giri, et al.. Genes suppressed by DNA methylation in non-small cell lung cancer reveal the epigenetics of epithelial-mesenchymal transition.. BMC Genomics, BioMed Central, 2013, 15, pp.1079. 〈inserm-01122392〉

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