Abstract
Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis, rapid development of resistance to chemotherapy and genetic instability. This study profiles DNA methylation in SCLC, patient-derived xenografts (PDX) and cell lines at single-nucleotide resolution. DNA methylation patterns of primary samples are distinct from those of cell lines, whereas PDX maintain a pattern closely consistent with primary samples. Clustering of DNA methylation and gene expression of primary SCLC revealed distinct disease subtypes among histologically indistinguishable primary patient samples with similar genetic alterations. SCLC is notable for dense clustering of high-level methylation in discrete promoter CpG islands, in a pattern clearly distinct from other lung cancers and strongly correlated with high expression of the E2F target and histone methyltransferase gene EZH2. Pharmacologic inhibition of EZH2 in a SCLC PDX markedly inhibited tumor growth.
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Acknowledgements
We thank Inna Kodos in the Sloan Kettering Antitumor Assessment Core for her technical expertise. We are grateful to all members of the Rudin and Hann labs for thoughtful discussions. SU2C, P30 CA008748 gave financial support.
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CMR has been a paid consultant regarding cancer drug development for AbbVie, Aveo, Celgene, GlaxoSmithKline and Merck. The remaining authors declare no conflict of interest.
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Poirier, J., Gardner, E., Connis, N. et al. DNA methylation in small cell lung cancer defines distinct disease subtypes and correlates with high expression of EZH2. Oncogene 34, 5869–5878 (2015). https://doi.org/10.1038/onc.2015.38
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DOI: https://doi.org/10.1038/onc.2015.38
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