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Ronchi, C.L.* ; Peverelli, E.* ; Herterich, S.* ; Weigand, I.* ; Mantovani, G.* ; Schwarzmayr, T. ; Sbiera, S.* ; Allolio, B.* ; Honegger, J.* ; Appenzeller, S.* ; Lania, A.* ; Reincke, M.* ; Calebiro, D.* ; Spada, A.* ; Buchfelder, M.* ; Flitsch, J.* ; Strom, T.M.* ; Fassnacht, M.*

Landscape of somatic mutations in sporadic GH-secreting pituitary adenomas.

Eur. J. Endocrinol. 174, 363-372 (2016)
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CONTEXT: Alterations in the cAMP signalling pathway are common in hormonally-active endocrine tumors. Somatic mutations at GNAS are causative in 30-40% of GH-secreting adenomas. Recently, mutations affecting the USP8 and PRKACA gene have been reported in ACTH-secreting pituitary adenomas and cortisol-secreting adrenocortical adenomas, respectively. However, the pathogenesis of many GH-secreting adenomas remains unclear. AIM: Comprehensive genetic characterization of sporadic GH-secreting adenomas and identification of new driver mutations. DESIGN: Screening for somatic mutations was performed in 67 GH-secreting adenomas by targeted sequencing for GNAS, PRKACA, and USP8 mutations (n=31) and next-generation exome-sequencing (n=36). RESULTS: By targeted sequencing known activating mutations in GNAS were detected in 5 cases (16.1%), while no somatic mutations were observed in both PRKACA and USP8. Whole exome sequencing identified 134 protein-altering somatic mutations in 31/36 tumors with a median of 3 mutations per sample (range: 1-13). The only recurrent mutations have been observed in GNAS (31.4% of cases). However, 7 genes involved in cAMP signalling pathway were affected in 14 of 36 samples and 8 samples harbored variants in genes involved in the calcium signaling or metabolism. At the enrichment analysis, several altered genes resulted to be associated with developmental processes. No correlation between genetic alterations and the clinical data was observed. CONCLUSIONS: This study provides a comprehensive analysis of somatic mutations in a large series of GH-secreting adenomas. No novel recurrent genetic alterations have been observed, but the data suggest that beside cAMP pathway calcium signalling might be involved in the pathogenesis of these tumors.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Protein-kinase-a; Adrenal Cushings-syndrome; Epidermal-growth-factor; Pka Catalytic Subunit; Somatotroph Adenomas; Regulatory Subunit; Adrenocortical Hyperplasia; Acromegalic Patients; Activating Mutation; Sequence-analysis
ISSN (print) / ISBN 0804-4643
e-ISSN 1479-683X
Journal European Journal of Endocrinology
Quellenangaben Volume: 174, Issue: 3, Pages: 363-372 Article Number: , Supplement: ,
Publisher BioScientifica
Publishing Place Bristol
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)