title: Wnt/β-catenin pathway activation in adrenocortical adenomas is frequently due to somatic CTNNB1-activating mutations, which are associated with larger and nonsecreting tumors: a study in cortisol-secreting and -nonsecreting tumors.
abstract: BACKGROUND
  Abnormal β-catenin immunohistochemistry and mutations of the β-catenin gene (CTNNB1) have been reported in adrenocortical adenomas (ACAs), but the frequencies of these defects and the phenotype of such tumors have not been clearly determined.
  
  
  OBJECTIVE
  The objective of the study was to describe the Wnt/β-catenin pathway alterations in 100 ACAs and their association with clinicopathological characteristics.
  
  
  METHODS
  One hundred consecutive ACAs (excluding Conn's adenomas) were studied clinically by β-catenin immunohistochemistry and direct sequencing of CTNNB1.
  
  
  RESULTS
  Thirty-five ACAs were nonsecreting adenomas (NSAs), 19 were subclinical cortisol secreting adenomas (SCSAs), and 46 were cortisol secreting adenomas (CSAs). Fifty-one tumors had abnormal cytoplasmic and/or nuclear β-catenin immunohistochemical staining, indicating Wnt/β-catenin pathway alteration. Thirty-six tumors showed CTNNB1 mutations, which all showed abnormal immunohistochemical β-catenin accumulation. Among the 64 nonmutated tumors, only 15 (23%) showed cytoplasmic and/or nuclear β-catenin staining (P < 0.0001). Tumors with CTNNB1 mutations were predominantly nonsecreting (61% NSAs, 22% SCSAs, 16% CSAs) whereas nonmutated tumors were predominantly secreting (20% NSAs, 17% SCSAs, 62% CSAs) (P < 0.0001). Mean tumor size and weight were, respectively, 4.2 cm (± 1.3) and 28.4 g (± 21.4) for tumors with CTNNB1 mutations vs. 3.4 cm (± 0.9) and 18.2 g (± 8.2) for nonmutated tumors (P < 0.01).
  
  
  CONCLUSIONS
  Abnormal cytoplasmic and/or nuclear β-catenin immunohistochemical staining occurs in about half of ACAs. This suggests the activation of the Wnt/β-catenin pathway, which could be explained by activating mutations of CTNNB1 in 70% of the cases. CTNNB1 mutations are mainly observed in larger and nonsecreting ACAs, suggesting that the Wnt/β-catenin pathway activation is associated with the development of less differentiated ACAs.
authors.affiliation: Department of Endocrinology, Metabolism, and Cancer, Institut National de la Santé et de la Recherche Médicale Unité 1016, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bonnet
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gaujoux
authors.forename: Pierre
authors.initials: P
authors.lastname: Launay
authors.forename: Camille
authors.initials: C
authors.lastname: Baudry
authors.forename: Ilham
authors.initials: I
authors.lastname: Chokri
authors.forename: Bruno
authors.initials: B
authors.lastname: Ragazzon
authors.forename: Rossella
authors.initials: R
authors.lastname: Libé
authors.forename: Fernande
authors.initials: F
authors.lastname: René-Corail
authors.forename: Anne
authors.initials: A
authors.lastname: Audebourg
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Vacher-Lavenu
authors.forename: Lionel
authors.initials: L
authors.lastname: Groussin
authors.forename: Xavier
authors.initials: X
authors.lastname: Bertagna
authors.forename: Bertrand
authors.initials: B
authors.lastname: Dousset
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Frédérique
authors.initials: F
authors.lastname: Tissier
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics* / Q000502:physiology*; D010641:Phenotype; D012334:RNA, Neoplasm / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D051153:Wnt Proteins / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics*
chemical_list: C495270:CTNNB1 protein, human; D004273:DNA, Neoplasm; D012334:RNA, Neoplasm; D051153:Wnt Proteins; D051176:beta Catenin; D006854:Hydrocortisone