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Mutations of β-Catenin in Adrenocortical Tumors: Activation of the Wnt Signaling Pathway Is a Frequent Event in both Benign and Malignant Adrenocortical Tumors

Authors :
Catherine Cavard
Christine Gicquel
E. Jullian
Gwladys Fumey
Lionel Groussin
Jérôme Bertherat
Anne-Marie Hagnere
Xavier Bertagna
Karine Perlemoine
Frédérique Tissier
Marie-Cécile Vacher-Lavenu
Christine Perret
Fernande René-Corail
Source :
Cancer Research. 65:7622-7627
Publication Year :
2005
Publisher :
American Association for Cancer Research (AACR), 2005.

Abstract

Adrenocortical cancer is a rare cancer with a very poor prognosis. The genetic alterations identified to date in adrenocortical tumors are limited. Activating mutations of the Wnt signaling pathway have been observed in more frequent cancers, particularly digestive tract tumors. We investigated whether Wnt pathway activation is involved in adrenocortical tumorigenesis. In a series of 39 adrenocortical tumors, immunohistochemistry revealed abnormal cytoplasmic and/or nuclear accumulation of β-catenin in 10 of 26 adrenocortical adenomas and in 11 of 13 adrenocortical carcinomas. An activating somatic mutation of the β-catenin gene was shown in 7 of 26 adrenocortical adenomas and in 4 of 13 adrenocortical carcinomas; these mutations were observed only in adrenocortical tumors with abnormal β-catenin accumulation and most were point mutations altering the Ser45 of exon 3 (in the consensus GSK3-β/CK1 phosphorylation site). Functional studies showed that the activating Ser45 β-catenin mutation found in the adrenocortical cancer H295R cell line leads to constitutive activation of T-cell factor–dependent transcription. This is the first molecular defect to be reported with the same prevalence in both benign (27%) and malignant (31%) adrenocortical tumors. β-Catenin mutations are also the most frequent genetic defect currently known in adrenocortical adenomas. In adrenocortical adenomas, β-catenin alterations are more frequent in nonfunctioning tumors, suggesting that β-catenin pathway activation might be mostly involved in the development of nonsecreting adrenocortical adenomas and adrenocortical carcinomas. The very frequent and substantial accumulation of β-catenin in adrenocortical carcinomas suggests that other alterations might also be involved. This finding may contribute to new therapeutic approaches targeting the Wnt pathway in malignant adrenocortical tumors, for which limited medical therapy is available.

Details

ISSN :
15387445 and 00085472
Volume :
65
Database :
OpenAIRE
Journal :
Cancer Research
Accession number :
edsair.doi.dedup.....deaf3fbd254e31a10e0110dd37bdccab
Full Text :
https://doi.org/10.1158/0008-5472.can-05-0593