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Identification of Myc target genes in xenograft tissue derived from human lung cancers

ABSTRACT: All three transforming members of the Myc family play a significant role in the development of both SCLC and NSCLC. NSCLC constitutes 80% of all lung cancer, and cMyc expression is most often deregulated, compared with N-Myc and L-Myc, in this disease. Thus, although we are interested in understanding the regulation and function of the entire Myc family in all lung cancers, we focused our research on cMyc deregulation in NSCLC. To identify target genes whose regulatory regions are bound in response to deregulated cMyc in NSCLC, we analyzed mouse xenograft tumours established in immune-compromised mice from monolayer cell lines derived from primary adenocarcinoma NSCLCs. These xenografts were chosen for further study because they show a genetic profile similar to their respective primary tumour (MGH8, RVH6849, A549, MGH24). High c-myc expression positively correlates with the ability of NSCLC cell lines to form xenografts, suggesting that Myc contributes towards the ability of the cells to grow in vivo. We conducted Myc-specific ChIP-chip and the corresponding normal IgG control using the Agilent genome-wide oligonucleotide promoter arrays on 3 biological replicates, of each of the four xenograft tumours. Following pre-processing using variance-stabilizing normalization and statistical analysis using general linear models we identified a list of 2,207 genes significantly enriched for c-Myc binding.

ORGANISM(S): Homo sapiens

PROVIDER: GSE15002 | GEO | 2009/11/24

SECONDARY ACCESSION(S): PRJNA114717

REPOSITORIES: GEO

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Project description:PURPOSE: Non-small cell lung cancers (NSCLC) comprise multiple distinct biological groups with different prognoses. For example, patients with epithelial-like (EL) tumors have a better prognosis and exhibit greater sensitivity to inhibitors of the epidermal growth factor receptor (EGFR) pathway than patients with mesenchymal-like (ML) tumors. Here we test the hypothesis that EL NSCLCs can be distinguished from ML NSCLCs on the basis of global DNA methylation patterns. EXPERIMENTAL DESIGN: To determine whether phenotypic subsets of NSCLC can be defined based on their DNA methylation patterns, we combined microfluidics-based gene expression analysis and genome-wide methylation profiling. We derived robust classifiers for both gene expression and methylation in cell lines and tested these classifiers in surgically resected NSCLC tumors. We validate our approach using quantitative RT-PCR and methylation specific PCR in formalin-fixed biopsies from NSCLC patients who went on to fail front-line chemotherapy. RESULTS: We show that patterns of methylation divide NSCLCs into EL and ML subsets as defined by gene expression and that these signatures are similarly correlated in NSCLC cell lines and tumors. We identify multiple DMRs, including ERBB2 and ZEB2, whose methylation status is strongly associated with an epithelial phenotype in NSCLC cell lines, surgically resected tumors, and formalin-fixed biopsies from NSCLC patients who went on to fail front-line chemotherapy. CONCLUSIONS: Our data demonstrate that patterns of DNA methylation can divide NSCLCs into two phenotypically distinct subtypes of tumors and provide proof of principle that differences in DNA methylation can be used for predictive biomarker discovery and development. To determine whether phenotypic subsets of NSCLC can be defined based on their DNA methylation patterns, we combined microfluidics-based gene expression analysis and genome-wide methylation profiling. We derived robust classifiers for both gene expression and methylation in cell lines and tested these classifiers in surgically resected NSCLC tumors. We validate our approach using quantitative RT-PCR and methylation specific PCR in formalin-fixed biopsies from NSCLC patients who went on to fail front-line chemotherapy.

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Identification of Myc target genes in xenograft tissue derived from human lung cancers

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