title: Genome-wide CpG island methylation analyses in non-small cell lung cancer patients.
abstract: 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.
authors.affiliation: Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna 1090, Austria. gerwin.heller@meduniwien.ac.at
authors.forename: Gerwin
authors.initials: G
authors.lastname: Heller
authors.forename: Valerie N
authors.initials: VN
authors.lastname: Babinsky
authors.forename: Barbara
authors.initials: B
authors.lastname: Ziegler
authors.forename: Marlene
authors.initials: M
authors.lastname: Weinzierl
authors.forename: Christian
authors.initials: C
authors.lastname: Noll
authors.forename: Corinna
authors.initials: C
authors.lastname: Altenberger
authors.forename: Leonhard
authors.initials: L
authors.lastname: Müllauer
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dekan
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Grin
authors.forename: György
authors.initials: G
authors.lastname: Lang
authors.forename: Adelheid
authors.initials: A
authors.lastname: End-Pfützenreuter
authors.forename: Irene
authors.initials: I
authors.lastname: Steiner
authors.forename: Sonja
authors.initials: S
authors.lastname: Zehetmayer
authors.forename: Balazs
authors.initials: B
authors.lastname: Döme
authors.forename: Britt-Madeleine
authors.initials: BM
authors.lastname: Arns
authors.forename: Kwun M
authors.initials: KM
authors.lastname: Fong
authors.forename: Casey M
authors.initials: CM
authors.lastname: Wright
authors.forename: Ian A
authors.initials: IA
authors.lastname: Yang
authors.forename: Walter
authors.initials: W
authors.lastname: Klepetko
authors.forename: Martin
authors.initials: M
authors.lastname: Posch
authors.forename: Christoph C
authors.initials: CC
authors.lastname: Zielinski
authors.forename: Sabine
authors.initials: S
authors.lastname: Zöchbauer-Müller
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D001483:Base Sequence; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D002874:Chromosome Mapping; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012372:ROC Curve; D017422:Sequence Analysis, DNA; D059467:Transcriptome
chemical_list: D015820:Cadherins; D018398:Homeodomain Proteins; C074437:EVX1 protein, human