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J Clin Endocrinol Metab. 2011 Oct;96(10):3106-14. doi: 10.1210/jc.2011-0363. Epub 2011 Aug 17.

Wnt/beta-catenin pathway deregulation in childhood adrenocortical tumors.

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1
Department of Pediatrics, School of Medicine of Ribeirao Preto, University of Sao Paulo, 14049-900 Sao Paulo, Brazil.

Abstract

CONTEXT:

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.

PATIENTS AND 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.

PMID:
21849527
DOI:
10.1210/jc.2011-0363
[Indexed for MEDLINE]
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