title: The role of epigenetic modification in tumorigenesis and progression of pituitary adenomas: a systematic review of the literature.
abstract: BACKGROUND
  Pituitary adenomas (PAs) are commonly occurring neoplasms with diverse endocrine and neurological effects. Although somatic gene mutations are uncommon in sporadic PAs, recent studies lend support to epigenetic modification as a potential cause of tumorigenesis and tumor progression.
  
  
  METHODS
  A systematic literature review of the PubMed and Google Scholar databases was conducted to identify abstracts (n=1,082) pertaining to key targets and mechanisms implicated in epigenetic dysregulation of PAs published between 1993-2013. Data regarding histopathological subtype, target genes, mode of epigenetic modification, and clinical correlation were recorded and analyzed.
  
  
  RESULTS
  Of the 47 that studies met inclusion criteria and focused on epigenomic assessment of PAs, only 2 were genome-scale analyses. Current evidence supports epigenetic alteration in at least 24 PA genes, which were categorized into four groups based on function and epigenetic alteration: 1) Sixteen tumor suppressor genes silenced via DNA methylation; 2) Two oncogenes overexpressed via histone acetylation and hypomethylation; 3) Three imprinted genes with selective allelic silencing; and 4) One epigenome writer inducing abnormal genome-scale activity and 5) Two transcription regulators indirectly modifying the genome. Of these, 5 genes (CDKN2A, GADD45y, FGFR2, caspase-8, and PTAG) showed particular susceptibility to epigenetic modification, with abnormal DNA methylation in >50% of PA samples. Several genes displayed correlations between epigenetic modification and clinically relevant parameters, including invasiveness (CDKN2A; DAPK; Rb1), sex (MAGE-A3), tumor size (GNAS1), and histopathological subtype (CDKN2A; MEG3; p27; RASSF1A; Rb1).
  
  
  CONCLUSIONS
  Epigenetic modification of selected PA genes may play a key role in tumorigenesis and progression, which may translate into important diagnostic and therapeutic applications.
authors.affiliation: Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Pease
authors.affiliation: Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Chao
authors.initials: C
authors.lastname: Ling
authors.affiliation: Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America ; Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: William J
authors.initials: WJ
authors.lastname: Mack
authors.affiliation: Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America ; Department of Psychiatry, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America ; Division of Bioinformatics, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America ; Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Zada
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D053181:Caspase 8 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D006801:Humans; D010911:Pituitary Neoplasms / Q000235:genetics*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; C496066:RHBDD3 protein, human; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D053181:Caspase 8