(American Association for Cancer Research (AACR), 2015) Neupane, Manish; Clark, Allison; Landini, S.; Birkbak, N; Eklund, A. C.; Lim, E.; Culhane, Aedin; Barry, William T.; Schumacher, Sandra; Beroukhim, Rameen; Szallasi, Zoltan; Vidal, Marc; Hill, David; Silver, Daniel P.
An unbiased genome-scale screen for unmutated genes that drive cancer growth when overexpressed identified MECP2 as a novel oncogene. MECP2 resides in a region of the Xchromosome 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 KRASG12Caddicted cell line after KRAS down-regulation, 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.
