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DNA hypermethylation in lung cancer is targeted at differentiation-associated genes

Oncogene volume 31, pages 1181–1188 (2012)Cite this article

Abstract

Aberrant DNA hypermethylation of tumor suppressor genes is thought to be an early event in tumorigenesis. Many studies have reported the methylation status of individual genes with known involvement in cancer, but an unbiased assessment of the biological function of the collective of hypermethylated genes has not been conducted so far. Based on the observation that a variety of human cancers recapitulate developmental gene expression patterns (that is activate genes normally expressed in early development and suppress late developmental genes), we hypothesized that the silencing of differentiation-associated genes in cancer could be attributed in part to DNA hypermethylation. To this end, we investigated the developmental expression patterns of genes with hypermethylated CpG islands in primary human lung carcinomas and lung cancer cell lines. We found that DNA hypermethylation primarily affects genes that are expressed in late stages of murine lung development. Gene ontology characterization of these genes shows that they are almost exclusively involved in morphogenetic differentiation processes. Our results indicate that DNA hypermethylation in cancer functions as a selective silencing mechanism of genes that are required for the maintenance of a differentiated state. The process of cellular de-differentiation that is evident on both the microscopic and transcriptional level in cancer might at least partly be mediated by these epigenetic events. Our observations provide a mechanistic explanation for induction of differentiation upon treatment with DNA methyltransferase inhibitors.

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Acknowledgements

We would like to thank David Page, Simon Kasif and Annina Deleo for valuable discussion.

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Authors and Affiliations

  1. Harvard-MIT Division of Health Sciences and Technology, Bioinformatics & Integrative Genomics, Cambridge, MA, USA

    E Helman & I S Kohane

  2. Department of Radiation Oncology, Edwin L. Steele Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    K Naxerova

  3. Children's Hospital Informatics Program, Boston, MA, USA

    I S Kohane

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  1. E Helman
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  2. K Naxerova
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  3. I S Kohane
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Correspondence to I S Kohane.

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Helman, E., Naxerova, K. & Kohane, I. DNA hypermethylation in lung cancer is targeted at differentiation-associated genes. Oncogene 31, 1181–1188 (2012). https://doi.org/10.1038/onc.2011.307

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