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

Steven H. Lin, Jing Wang, Pierre Saintigny, Chia Chin Wu, Uma Giri, Jing Zhang, Toshi Menju, Lixia Diao, Lauren Byers, John N. Weinstein, Kevin R. Coombes, Luc Girard, Ritsuko Komaki, Ignacio I. Wistuba, Hiroshi Date, John D. Minna, John V. Heymach

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish (US)
Article number1079
JournalBMC Genomics
Volume15
Issue number1
DOIs
StatePublished - Dec 8 2014

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Epithelial-Mesenchymal Transition
DNA Methylation
Epigenomics
Non-Small Cell Lung Carcinoma
Genes
Transcriptome
Gene Expression
Cell Line
Methylation
Lung Neoplasms
Neoplasms
Azacitidine
Cluster Analysis
Epithelial Cells
Neoplasm Metastasis
Phenotype

Keywords

  • DNA methylation
  • Epithelial-mesenchymal transition
  • Erlotinib
  • Lung cancer

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

Cite this

Genes suppressed by DNA methylation in non-small cell lung cancer reveal the epigenetics of epithelial-mesenchymal transition. / Lin, Steven H.; Wang, Jing; Saintigny, Pierre; Wu, Chia Chin; Giri, Uma; Zhang, Jing; Menju, Toshi; Diao, Lixia; Byers, Lauren; Weinstein, John N.; Coombes, Kevin R.; Girard, Luc; Komaki, Ritsuko; Wistuba, Ignacio I.; Date, Hiroshi; Minna, John D.; Heymach, John V.

In: BMC Genomics, Vol. 15, No. 1, 1079, 08.12.2014.

Research output: Contribution to journalArticle

Lin, SH, Wang, J, Saintigny, P, Wu, CC, Giri, U, Zhang, J, Menju, T, Diao, L, Byers, L, Weinstein, JN, Coombes, KR, Girard, L, Komaki, R, Wistuba, II, Date, H, Minna, JD & Heymach, JV 2014, 'Genes suppressed by DNA methylation in non-small cell lung cancer reveal the epigenetics of epithelial-mesenchymal transition', BMC Genomics, vol. 15, no. 1, 1079. https://doi.org/10.1186/1471-2164-15-1079.
Lin, Steven H. ; Wang, Jing ; Saintigny, Pierre ; Wu, Chia Chin ; Giri, Uma ; Zhang, Jing ; Menju, Toshi ; Diao, Lixia ; Byers, Lauren ; Weinstein, John N. ; Coombes, Kevin R. ; Girard, Luc ; Komaki, Ritsuko ; Wistuba, Ignacio I. ; Date, Hiroshi ; Minna, John D. ; Heymach, John V. / Genes suppressed by DNA methylation in non-small cell lung cancer reveal the epigenetics of epithelial-mesenchymal transition. In: BMC Genomics. 2014 ; Vol. 15, No. 1.
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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.",
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AU - Lin, Steven H.

AU - Wang, Jing

AU - Saintigny, Pierre

AU - Wu, Chia Chin

AU - Giri, Uma

AU - Zhang, Jing

AU - Menju, Toshi

AU - Diao, Lixia

AU - Byers, Lauren

AU - Weinstein, John N.

AU - Coombes, Kevin R.

AU - Girard, Luc

AU - Komaki, Ritsuko

AU - Wistuba, Ignacio I.

AU - Date, Hiroshi

AU - Minna, John D.

AU - Heymach, John V.

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N2 - 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.

AB - 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.

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KW - Epithelial-mesenchymal transition

KW - Erlotinib

KW - Lung cancer

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