title: Wnt/beta-catenin and 3',5'-cyclic adenosine 5'-monophosphate/protein kinase A signaling pathways alterations and somatic beta-catenin gene mutations in the progression of adrenocortical tumors.
abstract: BACKGROUND
  The Wnt/beta-catenin and cAMP signaling pathways play an important role in adrenal cortex tumorigenesis. Somatic activating mutations of the beta-catenin gene (CTNNB1) are the most frequent genetic defects identified both in adrenocortical adenomas (ACAs) and adrenocortical cancers (ACCs). PRKAR1A mutations leading to cAMP pathway dysregulation are observed in primary pigmented nodular adrenocortical diseases (PPNADs) and some sporadic ACAs.
  
  
  OBJECTIVE
  The objective of the investigation was to study Wnt/beta-catenin dysregulation in adrenocortical tumors (ACTs) with cAMP pathway genetic alteration and search for secondary CTNNB1 somatic mutations in heterogeneous tumors.
  
  
  METHODS
  Nine PPNADs, including five with macronodules, three ACAs with PRKAR1A somatic mutations, and one heterogeneous tumor with ACC developed within an ACA, were studied by immunohistochemistry and DNA sequencing.
  
  
  RESULTS
  beta-Catenin accumulation was observed in all PPNADs, ACAs with PRKAR1A mutations, and the ACC component of the heterogeneous tumor. CTNNB1 somatic activating mutations were found in the macronodule of two of the five macronodular PPNADs, in one ACA with a PRKAR1A somatic mutation, and in the malignant part of the heterogeneous ACT.
  
  
  CONCLUSIONS
  The Wnt/beta-catenin pathway is activated in PPNADs and ACAs with PRKAR1A mutations, suggesting a cross talk between the cAMP and Wnt/beta-catenin pathways in ACT development. In addition, the occurrence as an additional hit of a CTNNB1 somatic mutation is associated with larger or more aggressive ACTs. This underlines the importance of the Wnt/beta-catenin pathway in adrenal cortex tumorigenesis and the importance of genetic accumulation in the progression of ACTs.
authors.affiliation: Service des Maladies Endocriniennes et Métaboliques, Hôpital Cochin, 75014 Paris, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gaujoux
authors.forename: Frédérique
authors.initials: F
authors.lastname: Tissier
authors.forename: Lionel
authors.initials: L
authors.lastname: Groussin
authors.forename: Rossella
authors.initials: R
authors.lastname: Libé
authors.forename: Bruno
authors.initials: B
authors.lastname: Ragazzon
authors.forename: Pierre
authors.initials: P
authors.lastname: Launay
authors.forename: Anne
authors.initials: A
authors.lastname: Audebourg
authors.forename: Bertrand
authors.initials: B
authors.lastname: Dousset
authors.forename: Xavier
authors.initials: X
authors.lastname: Bertagna
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D000242:Cyclic AMP / Q000378:metabolism; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D009361:Neoplasm Invasiveness; D015398:Signal Transduction / Q000235:genetics*; D047368:Tumor Burden / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D051153:Wnt Proteins; D051176:beta Catenin; D000242:Cyclic AMP