DNA methylation in small cell lung cancer defines distinct disease subtypes and correlates with high expression of EZH2.
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.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
J T
JT
Poirier
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, USA.
E E
EE
Gardner
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
N
N
Connis
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
A L
AL
Moreira
Molecular Pharmacology & Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
E
E
de Stanchina
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
C L
CL
Hann
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, USA.
C M
CM
Rudin
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D018899:CpG Islands; D019175:DNA Methylation; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000145:classification* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055752:Small Cell Lung Carcinoma / Q000145:classification* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2