title: MECP2 Is a Frequently Amplified Oncogene with a Novel Epigenetic Mechanism That Mimics the Role of Activated RAS in Malignancy.
abstract: An unbiased genome-scale screen for unmutated genes that drive cancer growth when overexpressed identified methyl cytosine-guanine dinucleotide (CpG) binding protein 2 (MECP2) as a novel oncogene. MECP2 resides in a region of the X-chromosome that is significantly amplified across 18% of cancers, and many cancer cell lines have amplified, overexpressed MECP2 and are dependent on MECP2 expression for growth. MECP2 copy-number gain and RAS family member alterations are mutually exclusive in several cancer types. The MECP2 splicing isoforms activate the major growth factor pathways targeted by activated RAS, the MAPK and PI3K pathways. MECP2 rescued the growth of a KRAS(G12C)-addicted cell line after KRAS downregulation, and activated KRAS rescues the growth of an MECP2-addicted cell line after MECP2 downregulation. MECP2 binding to the epigenetic modification 5-hydroxymethylcytosine is required for efficient transformation. These observations suggest that MECP2 is a commonly amplified oncogene with an unusual epigenetic mode of action.
  
  
  CONCLUSIONS
  MECP2 is a commonly amplified oncogene in human malignancies with a unique epigenetic mechanism of action. Cancer Discov; 6(1); 45-58. ©2015 AACR.This article is highlighted in the In This Issue feature, p. 1.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Manish
authors.initials: M
authors.lastname: Neupane
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Allison P
authors.initials: AP
authors.lastname: Clark
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Serena
authors.initials: S
authors.lastname: Landini
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Nicolai J
authors.initials: NJ
authors.lastname: Birkbak
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Aron C
authors.initials: AC
authors.lastname: Eklund
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: Elgene
authors.initials: E
authors.lastname: Lim
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Aedin C
authors.initials: AC
authors.lastname: Culhane
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: William T
authors.initials: WT
authors.lastname: Barry
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Schumacher
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. Broad Institute of Harvard and MIT, Cambridge, Massachusetts. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark. Children's Hospital Informatics Program at the Harvard-MIT Division of Health Sciences and Technology, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szallasi
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Genetics, Harvard Medical School, Boston, Massachusetts.
authors.forename: Marc
authors.initials: M
authors.lastname: Vidal
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Genetics, Harvard Medical School, Boston, Massachusetts.
authors.forename: David E
authors.initials: DE
authors.lastname: Hill
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Daniel_Silver@dfci.harvard.edu.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Silver
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D017398:Alternative Splicing; D000818:Animals; D045744:Cell Line, Tumor; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005784:Gene Amplification; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics*; D020033:Protein Isoforms / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics*
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D020033:Protein Isoforms; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D018631:ras Proteins