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Characterizing the molecular spatial and temporal field of injury in early stage smoker non-small cell lung cancer patients after definitive surgery by expression profiling

ABSTRACT: Gene expression alterations in response to cigarette smoke have been characterized in normal-appearing bronchial epithelium of healthy smokers and it has been suggested that adjacent histologically normal tissue display tumor-associated molecular abnormalities. We sought to delineate the spatial and temporal molecular lung field of injury in smoker early stage non-small cell lung cancer (NSCLC) patients (n=19) who were accrued into a surveillance clinical trial for annual follow-up and bronchoscopies within one year after definitive surgery.

ORGANISM(S): Homo sapiens

PROVIDER: GSE40407 | GEO | 2012/12/01

SECONDARY ACCESSION(S): PRJNA173894

REPOSITORIES: GEO

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Project description:Epigenetic alterations are widespread in cancer and can complement genetic alterations to influence cancer progression and treatment. To better understand the potential contribution of DNA methylation alterations to tumor phenotype in non-small cell lung cancer (NSCLC) in both smoker and never-smoker patients, we performed a comprehensive, genome-wide profiling of DNA methylation in 17 primary non-small cell lung cancer and 10 matched normal lung samples using the complementary methylation assays MeDIP-seq and MRE-seq. Compared to patient-matched non-malignant lung tissue, we report recurrent methylation changes of several gene promoters, many previously implicated in cancer, including FAM83A and SEPT9 (hypomethylation), and PCDH7, NKX2-1, and SOX17 (hypermethylation). Although smoker and never-smoker patients shared many methylation changes, several were specific and recurrent within a particular smoking status. In particular, never-smokers displayed a greater proportion of hypoDMRs and exhibited a greater number of recurrently hypomethylated promoters, including the promoter of the oncogene ASPSCR1, and others previously linked to cancer, including TOP2A, DPP9, and USP39. Methylation changes outside of promoters were also widespread and often recurrent, particularly the loss of methylation over repetitive elements, highly enriched for ERV1 subfamilies. Recurrent hypoDMRs were also enriched for several transcription factor (TF) binding motifs, often for genes involved in signaling and cell proliferation, including 71% encoding a binding site of NKX2-1, which was found to be significantly upregulated in TCGA LUAD samples. Furthermore, the overwhelming majority of DMRs identified in this study were found to reside in an active chromatin state in at least one tissue profiled using the Roadmap Epigenome data, suggesting that methylation changes may contribute to altered regulatory programs through the adaptation of cell type-specific expression programs.

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Characterizing the molecular spatial and temporal field of injury in early stage smoker non-small cell lung cancer patients after definitive surgery by expression profiling

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