HOXA2 and HOXA10 methylation may serve as prognostic parameters in squamous cell lung cancer patients

http://www.ncbi.nlm.nih.gov/pubmed/23172663

Carcinogenesis. 2012 Nov 19. [Epub ahead of print]

GENOME-WIDE CpG ISLAND METHYLATION ANALYSES IN NON-SMALL CELL LUNG CANCER PATIENTS.

Heller G, Babinsky VN, Ziegler B, Weinzierl M, Noll C, Altenberger C, Müllauer L, Dekan G, Grin Y, Lang G, End-Pfützenreuter A, Steiner I, Zehetmayer S, Döme B, Arns BM, Fong KM, Wright CM, Yang IA, Klepetko W, Posch M, Zielinski CC, Zöchbauer-Müller S.

Source

Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna (MUV), Vienna, Austria.

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 stage I-III non-small cell lung cancer(NSCLC) patients by combining methylated DNA immunoprecipitation and microarray analysis (MeDIP-chip). Overall, we identified 2414 genomic positions differentially methylated between tumor and non-malignant lung tissue samples. Ninety-seven % 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 analysed by gene expression microarrays suggesting that about one third of these genes are transcriptionally regulated by methylation. Moreover, comparison of methylation results with certain clinico-pathological 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.