title: Activation of cyclic AMP signaling leads to different pathway alterations in lesions of the adrenal cortex caused by germline PRKAR1A defects versus those due to somatic GNAS mutations.
abstract: BACKGROUND
  The overwhelming majority of benign lesions of the adrenal cortex leading to Cushing syndrome are linked to one or another abnormality of the cAMP or protein kinase pathway. PRKAR1A-inactivating mutations are responsible for primary pigmented nodular adrenocortical disease, whereas somatic GNAS activating mutations cause macronodular disease in the context of McCune-Albright syndrome, ACTH-independent macronodular hyperplasia, and, rarely, cortisol-producing adenomas.
  
  
  OBJECTIVE
  The whole-genome expression profile (WGEP) of normal (pooled) adrenals, PRKAR1A- (3) and GNAS-mutant (3) was studied. Quantitative RT-PCR and Western blot were used to validate WGEP findings.
  
  
  RESULTS
  MAPK and p53 signaling pathways were highly overexpressed in all lesions against normal tissue. GNAS-mutant tissues were significantly enriched for extracellular matrix receptor interaction and focal adhesion pathways when compared with PRKAR1A-mutant (fold enrichment 3.5, P < 0.0001 and 2.1, P < 0.002, respectively). NFKB, NFKBIA, and TNFRSF1A were higher in GNAS-mutant tumors (P < 0.05). Genes related to the Wnt signaling pathway (CCND1, CTNNB1, LEF1, LRP5, WISP1, and WNT3) were overexpressed in PRKAR1A-mutant lesions.
  
  
  CONCLUSIONS
  WGEP analysis revealed that not all cAMP activation is the same: adrenal lesions harboring PRKAR1A or GNAS mutations share the downstream activation of certain oncogenic signals (such as MAPK and some cell cycle genes) but differ substantially in their effects on others.
authors.affiliation: Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USA.
authors.forename: Madson Q
authors.initials: MQ
authors.lastname: Almeida
authors.forename: Monalisa F
authors.initials: MF
authors.lastname: Azevedo
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Xekouki
authors.forename: Eirini I
authors.initials: EI
authors.lastname: Bimpaki
authors.forename: Anelia
authors.initials: A
authors.lastname: Horvath
authors.forename: Michael T
authors.initials: MT
authors.lastname: Collins
authors.forename: Lefkothea P
authors.initials: LP
authors.lastname: Karaviti
authors.forename: George S
authors.initials: GS
authors.lastname: Jeha
authors.forename: Nisan
authors.initials: N
authors.lastname: Bhattacharyya
authors.forename: Chris
authors.initials: C
authors.lastname: Cheadle
authors.forename: Tonya
authors.initials: T
authors.lastname: Watkins
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bourdeau
authors.forename: Maria
authors.initials: M
authors.lastname: Nesterova
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000302:Adrenal Cortex / Q000378:metabolism / Q000473:pathology; D000306:Adrenal Cortex Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000309:Adrenal Insufficiency / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000308:Adrenocortical Hyperfunction / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D002864:Chromogranins; D018389:Codon, Nonsense; D000242:Cyclic AMP / Q000378:metabolism*; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics* / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D018095:Germ-Line Mutation; D006801:Humans; D020935:MAP Kinase Signaling System; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015290:Second Messenger Systems; D060449:Wnt Signaling Pathway
chemical_list: D002864:Chromogranins; D018389:Codon, Nonsense; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C052131:extracellular matrix receptor; D000242:Cyclic AMP; D051416:Focal Adhesion Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs