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  • Oncogenomics
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The DNA methylation landscape of small cell lung cancer suggests a differentiation defect of neuroendocrine cells

Oncogene volume 32, pages 3559–3568 (2013)Cite this article

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Abstract

Small cell lung cancer (SCLC) is a disease characterized by aggressive clinical behavior and lack of effective therapy. Owing to its tendency for early dissemination, only a third of patients have limited-stage disease at the time of diagnosis. SCLC is thought to derive from pulmonary neuroendocrine cells. Although several molecular abnormalities in SCLC have been described, there are relatively few studies on epigenetic alterations in this type of tumor. Here, we have used methylation profiling with the methylated-CpG island recovery assay in combination with microarrays and conducted the first genome-scale analysis of methylation changes that occur in primary SCLC and SCLC cell lines. Among the hundreds of tumor-specifically methylated genes discovered, we identified 73 gene targets that are methylated in >77% of primary SCLC tumors, most of which have never been linked to aberrant methylation in tumors. These methylated targets have potential for biomarker development for early detection and therapeutic management of SCLC. SCLC cell lines had a greater number of hypermethylated genes than primary tumors. Gene ontology analysis indicated a significant enrichment of methylated genes functioning as transcription factors and in processes of neuronal differentiation. Motif analysis of tumor-specific methylated regions identified enrichment of binding sites for several neural cell fate-specifying transcription factors including NEUROD1, HAND1, ZNF423 and REST. We hypothesize that two potential mechanisms, loss of cell fate-determining transcription factors by methylation of their promoters and functional inactivation of their corresponding genomic-binding sites by DNA methylation, can promote a differentiation defect of neuroendocrine cells thus enhancing the ability of tumor progenitor cells to transition toward SCLC.

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Acknowledgements

We thank Steven Bates for culturing SCLC cell lines. This work was supported by the National Institutes of Health grant CA084469 to GPP and by generous funds from an anonymous donor.

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Author notes

  1. K H Kernstine

    Present address: 5Current address: Division of Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.,

  2. S Kalari and M Jung: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA, USA

    S Kalari, M Jung & G P Pfeifer

  2. Department Surgery, Beckman Research Institute of the City of Hope, Duarte, CA, USA

    K H Kernstine

  3. Division of Molecular Carcinogenesis, Nagoya University Graduate School of Medicine, Nagoya, Japan

    T Takahashi

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  1. S Kalari
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Correspondence to G P Pfeifer.

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Competing interests

Under a licensing agreement between City of Hope and Active Motif (Carlsbad, CA, USA), the MIRA technique was licensed to Active Motif, and the author GPP is entitled to a share of the royalties received by City of Hope from sales of the licensed technology. The rest of the authors declare no conflict of interest.

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Kalari, S., Jung, M., Kernstine, K. et al. The DNA methylation landscape of small cell lung cancer suggests a differentiation defect of neuroendocrine cells. Oncogene 32, 3559–3568 (2013). https://doi.org/10.1038/onc.2012.362

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