title: Wnt/beta-catenin pathway deregulation in childhood adrenocortical tumors.
abstract: BACKGROUND
  CTNNB1/β-catenin mutations and activation of Wnt/β-catenin pathway are frequent in adult adrenocortical tumors (ACT), but data on childhood ACT are lacking.
  
  
  OBJECTIVE
  The aim of the study was to investigate the presence of Wnt/β-catenin pathway abnormalities in childhood ACT.
  
  
  METHODS
  Clinicopathological findings and outcome of 62 childhood ACT patients were analyzed regarding CTNNB1 mutations and the expression of Wnt-related genes (CTNNB1; WNT4, a Wnt ligand; SFRP1, DKK3, and AXIN1, Wnt inhibitors; TCF7, a transcription factor; and MYC and WISP2, target genes) by quantitative PCR and immunohistochemistry.
  
  
  RESULTS
  CTNNB1-activating mutations were found in only four of 62 ACT (6%), all of them harboring TP53 mutation. There was association between the presence of CTNNB1 mutations and death (P = 0.02). Diffuse β-catenin accumulation was found in 71% of ACT, even in ACT without CTNNB1 mutations. Compared to normal adrenals, ACT presented increased expression of CTNNB1 (P = 0.008) and underexpression of Wnt inhibitor genes: DKK3 (P < 0.0001), SFRP1 (P = 0.05), and AXIN1 (P = 0.04). With regard to Wnt/β-catenin target genes, ACT presented increased expression of WISP2 but lower expression of MYC. Higher overall survival was associated with underexpression of SFRP1 (P = 0.01), WNT4 (P = 0.004), and TCF7 (P < 0.01).
  
  
  CONCLUSIONS
  CTNNB1 mutations are not common in childhood ACT but appear to associate with poor prognosis. Nevertheless, most ACT exhibit increased expression of β-catenin and WISP2 and reduced expression of Wnt inhibitor genes (DKK3, SFRP1, and AXIN1). Thus, in addition to CTNNB1 mutations, other genetic events affecting the Wnt/β-catenin pathway may be involved in childhood adrenocortical tumorigenesis.
authors.affiliation: Department of Pediatrics, School of Medicine of Ribeirao Preto, University of Sao Paulo, 14049-900 Sao Paulo, Brazil.
authors.forename: Letícia F
authors.initials: LF
authors.lastname: Leal
authors.forename: Lívia M
authors.initials: LM
authors.lastname: Mermejo
authors.forename: Leandra Z
authors.initials: LZ
authors.lastname: Ramalho
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Martinelli
authors.forename: José A
authors.initials: JA
authors.lastname: Yunes
authors.forename: Ana Luiza
authors.initials: AL
authors.lastname: Seidinger
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Mastellaro
authors.forename: Izilda A
authors.initials: IA
authors.lastname: Cardinalli
authors.forename: Silvia R
authors.initials: SR
authors.lastname: Brandalise
authors.forename: Ayrton C
authors.initials: AC
authors.lastname: Moreira
authors.forename: Luiz G
authors.initials: LG
authors.lastname: Tone
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Scrideli
authors.forename: Margaret
authors.initials: M
authors.lastname: Castro
authors.forename: Sonir R
authors.initials: SR
authors.lastname: Antonini
mesh_terms: D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000235:genetics / Q000378:metabolism*; D060466:Axin Protein / Q000502:physiology; D055511:CCN Intercellular Signaling Proteins; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D008297:Male; D009154:Mutation / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000302:isolation & purification; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D016019:Survival Analysis; D051822:T Cell Transcription Factor 1 / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D060528:Wnt4 Protein / Q000502:physiology; D051176:beta Catenin / Q000235:genetics / Q000502:physiology*
chemical_list: C555451:AXIN1 protein, human; D060466:Axin Protein; D055511:CCN Intercellular Signaling Proteins; C413323:CCN5 protein, human; C495270:CTNNB1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012097:Repressor Proteins; D051822:T Cell Transcription Factor 1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C555581:WNT4 protein, human; D051153:Wnt Proteins; D060528:Wnt4 Protein; D051176:beta Catenin; D004247:DNA