Journal Article

Genome-wide CpG island methylation analyses in non-small cell lung cancer patients

Gerwin Heller, Valerie N. Babinsky, Barbara Ziegler, Marlene Weinzierl, Christian Noll, Corinna Altenberger, Leonhard Müllauer, Gerhard Dekan, Yuliya Grin, György Lang, Adelheid End-Pfützenreuter, Irene Steiner, Sonja Zehetmayer, Balazs Döme, Britt-Madeleine Arns, Kwun M. Fong, Casey M. Wright, Ian A. Yang, Walter Klepetko, Martin Posch, Christoph C. Zielinski and Sabine Zöchbauer-Müller

in Carcinogenesis

Volume 34, issue 3, pages 513-521
Published in print March 2013 | ISSN: 0143-3334
Published online November 2012 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgs363
Genome-wide CpG island methylation analyses in non-small cell lung cancer patients

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DNA methylation is part of the epigenetic gene regulation complex, which is relevant for the pathogenesis of cancer. We performed a genome-wide search for methylated CpG islands in tumors and corresponding non-malignant lung tissue samples of 101 stages I–III non-small cell lung cancer (NSCLC) patients by combining methylated DNA immunoprecipitation and microarray analysis. Overall, we identified 2414 genomic positions differentially methylated between tumor and non-malignant lung tissue samples. Ninety-seven percent of them were found to be tumor-specifically methylated. Annotation of these genomic positions resulted in the identification of 477 tumor-specifically methylated genes of which many are involved in regulation of gene transcription and cell adhesion. Tumor-specific methylation was confirmed by a gene-specific approach. In the majority of tumors, methylation of certain genes was associated with loss of their protein expression determined by immunohistochemistry. Treatment of NSCLC cells with epigenetically active drugs resulted in upregulated expression of many tumor-specifically methylated genes analyzed by gene expression microarrays suggesting that about one-third of these genes are transcriptionally regulated by methylation. Moreover, comparison of methylation results with certain clinicopathological characteristics of the patients suggests that methylation of HOXA2 and HOXA10 may be of prognostic relevance in squamous cell carcinoma (SCC) patients. In conclusion, we identified a large number of tumor-specifically methylated genes in NSCLC patients. Expression of many of them is regulated by methylation. Moreover, HOXA2 and HOXA10 methylation may serve as prognostic parameters in SCC patients. Overall, our findings emphasize the impact of methylation on the pathogenesis of NSCLCs.

Journal Article.  5901 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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