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Genome-wide DNA methylation profiling of non-small cell lung carcinomas

Rejane Hughes Carvalho12, Vanja Haberle3, Jun Hou14, Teus van Gent14, Supat Thongjuea3, Wilfred van IJcken5, Christel Kockx5, Rutger Brouwer5, Erikjan Rijkers5, Anieta Sieuwerts6, John Foekens6, Mirjam van Vroonhoven57, Joachim Aerts8, Frank Grosveld1249, Boris Lenhard3* and Sjaak Philipsen124*

Author Affiliations

1 Department of Cell Biology, ErasmusMC, PO Box 2040, Rotterdam, CA, 3000, The Netherlands

2 Center for Cancer Genomics, ErasmusMC, Rotterdam, The Netherlands

3 Department of Biology and Computational Biology Unit, Uni BCCS, University of Bergen, Hoyteknologisenteret, Thormohlensgate 55, Bergen, N-5008, Norway

4 Dutch Consortium for Systems Biology, ErasmusMC, Rotterdam, The Netherlands

5 Center for Biomics, ErasmusMC, Rotterdam, The Netherlands

6 Internal Oncology, ErasmusMC, Rotterdam, The Netherlands

7 Department of Bioinformatics, ErasmusMC, Rotterdam, The Netherlands

8 Department of Pulmonology, ErasmusMC, Rotterdam, The Netherlands

9 Center for Biomedical Genetics, ErasmusMC, Rotterdam, The Netherlands

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Epigenetics & Chromatin 2012, 5:9  doi:10.1186/1756-8935-5-9

Published: 22 June 2012

Abstract

Background

Non-small cell lung carcinoma (NSCLC) is a complex malignancy that owing to its heterogeneity and poor prognosis poses many challenges to diagnosis, prognosis and patient treatment. DNA methylation is an important mechanism of epigenetic regulation involved in normal development and cancer. It is a very stable and specific modification and therefore in principle a very suitable marker for epigenetic phenotyping of tumors. Here we present a genome-wide DNA methylation analysis of NSCLC samples and paired lung tissues, where we combine MethylCap and next generation sequencing (MethylCap-seq) to provide comprehensive DNA methylation maps of the tumor and paired lung samples. The MethylCap-seq data were validated by bisulfite sequencing and methyl-specific polymerase chain reaction of selected regions.

Results

Analysis of the MethylCap-seq data revealed a strong positive correlation between replicate experiments and between paired tumor/lung samples. We identified 57 differentially methylated regions (DMRs) present in all NSCLC tumors analyzed by MethylCap-seq. While hypomethylated DMRs did not correlate to any particular functional category of genes, the hypermethylated DMRs were strongly associated with genes encoding transcriptional regulators. Furthermore, subtelomeric regions and satellite repeats were hypomethylated in the NSCLC samples. We also identified DMRs that were specific to two of the major subtypes of NSCLC, adenocarcinomas and squamous cell carcinomas.

Conclusions

Collectively, we provide a resource containing genome-wide DNA methylation maps of NSCLC and their paired lung tissues, and comprehensive lists of known and novel DMRs and associated genes in NSCLC.

Keywords:
DNA Methylation; Epigenetics; MethylCap; Next generation sequencing; Non-small cell lung Cancer