title: Mutations of beta-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors.
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 beta-catenin in 10 of 26 adrenocortical adenomas and in 11 of 13 adrenocortical carcinomas. An activating somatic mutation of the beta-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 beta-catenin accumulation and most were point mutations altering the Ser45 of exon 3 (in the consensus GSK3-beta/CK1 phosphorylation site). Functional studies showed that the activating Ser45 beta-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. beta-Catenin mutations are also the most frequent genetic defect currently known in adrenocortical adenomas. In adrenocortical adenomas, beta-catenin alterations are more frequent in nonfunctioning tumors, suggesting that beta-catenin pathway activation might be mostly involved in the development of nonsecreting adrenocortical adenomas and adrenocortical carcinomas. The very frequent and substantial accumulation of beta-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.
authors.affiliation: Department of Endocrinology, Institut National de la Santé et de la Recherche Médicale U567, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, IFR116, René Descartes-Paris 5 University, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Tissier
authors.forename: Catherine
authors.initials: C
authors.lastname: Cavard
authors.forename: Lionel
authors.initials: L
authors.lastname: Groussin
authors.forename: Karine
authors.initials: K
authors.lastname: Perlemoine
authors.forename: Gwladys
authors.initials: G
authors.lastname: Fumey
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Hagneré
authors.forename: Fernande
authors.initials: F
authors.lastname: René-Corail
authors.forename: Eric
authors.initials: E
authors.lastname: Jullian
authors.forename: Christine
authors.initials: C
authors.lastname: Gicquel
authors.forename: Xavier
authors.initials: X
authors.lastname: Bertagna
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Vacher-Lavenu
authors.forename: Christine
authors.initials: C
authors.lastname: Perret
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D051153:Wnt Proteins; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D036341:Intercellular Signaling Peptides and Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin