Field cancerization in non-small cell lung cancer: implications in disease pathogenesis.
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ABSTRACT:
SUBMITTER: Kadara H
PROVIDER: S-EPMC5821032 | biostudies-literature | 2012 May
REPOSITORIES: biostudies-literature
Publications
Field cancerization in non-small cell lung cancer: implications in disease pathogenesis.
Kadara Humam H Wistuba Ignacio I II
Proceedings of the American Thoracic Society 20120501 2
Lung cancer, of which non-small cell lung cancer (NSCLC) composes the majority, is the leading cause of cancer-related deaths in the United States and worldwide. NSCLCs are tumors with complex biology that we have recently started to understand with the advent of various histological, transcriptomic, genomic, and proteomic technologies. However, the histological and molecular pathogenesis of this malignancy, in particular of adenocarcinomas, is still largely unknown. Earlier studies have highlig ...[more]
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Project description:BackgroundField cancerization is the process in which a population of normal or pre-malignant cells is affected by oncogenic alterations leading to progressive molecular changes that drive malignant transformation. Aberrant DNA methylation has been implicated in early cancer development in non-small cell lung cancer (NSCLC); however, studies on its role in field cancerization (FC) are limited. This study aims to identify FC-specific methylation patterns that could distinguish between pre-malignant lesions and tumor tissues in NSCLC.MethodsWe enrolled 52 patients with resectable NSCLC and collected resected tumor (TUM), tumor-adjacent (ADJ) and tumor-distant normal (DIS) tissue samples, among whom 36 qualified for subsequent analyses. Methylation levels were profiled by bisulfite sequencing using a custom lung-cancer methylation panel.ResultsADJ and DIS samples demonstrated similar methylation profiles, which were distinct from distinct from that of TUM. Comparison of TUM and DIS profiles led to identification of 1740 tumor-specific differential methylated regions (DMRs), including 1675 hypermethylated and 65 hypomethylated (adjusted P < 0.05). Six of the top 10 tumor-specific hypermethylated regions were associated with cancer development. We then compared the TUM, ADJ, and DIS to further identify the progressively aggravating aberrant methylations during cancer initiation and early development. A total of 332 DMRs were identified, including a predominant proportion of 312 regions showing stepwise increase in methylation levels as the sample drew nearer to the tumor (i.e. DIS < ADJ < TUM) and 20 regions showing a stepwise decrease pattern. Gene set enrichment analysis (GSEA) for KEGG and GO terms consistently suggested enrichment of DMRs located in transcription factor genes, suggesting a central role of epigenetic regulation of transcription factors in FC and tumorigenesis.ConclusionWe revealed distinct methylation patterns between pre-malignant lesions and malignant tumors, suggesting the essential role of DNA methylation as an early step in pre-malignant field defects. Moreover, our study also identified differentially methylated genes, especially transcription factors, that could potentially be used as markers for lung cancer screening and for mechanistic studies of FC and early cancer development.
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Project description:Lung cancer (LC) is the leading cause of cancer death in men worldwide and has significantly increased in women. Differences in non-small cell lung cancer (NSCLC) behavior, prognosis, and response to treatment have been reported by sex and hormonal status, with premenopausal women presenting the worst prognosis compared to postmenopausal women and men. Additionally, the use of hormonal replacement therapy significantly increases NSCLC mortality; supporting the role of estrogen signaling in the pathogenesis of LC. The mechanisms by which estrogen promotes lung carcinogenesis have not been fully elucidated. Estrogen, through its receptor, can stimulate LC cell proliferation, death resistance, angiogenesis, migration and metastasis. Estrogen also induces expression of pro-inflammatory proteins and ligands that promote tumor evasion, suggesting that estrogen might modify the microenvironment and anti-tumor immune response. Recent reports have shown an interaction between the epidermal growth factor receptor (EGFR) pathway and estrogen signaling in lung adenocarcinoma, whence, combined treatment based on tyrosine kinase inhibitors (TKIs) and antiestrogen therapy is beginning to be evaluated. This review focuses on the differences in NSCLC behavior by sex and hormonal status, highlighting the role of estrogen and its receptors in lung carcinogenesis and LC prognosis. Due to the importance of estrogen in NSCLC development and progression we finally discuss the potential of antiestrogen therapy in LC treatment and show the results from preclinical and clinical trials.
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