Cristina L Ronchi1, Erika Peverelli2, Sabine Herterich2, Isabel Weigand2, Giovanna Mantovani2, Thomas Schwarzmayr2, Silviu Sbiera2, Bruno Allolio2, Jürgen Honegger2, Silke Appenzeller3, Andrea G Lania2, Martin Reincke2, Davide Calebiro2, Anna Spada2, Michael Buchfelder2, Joerg Flitsch2, Tim M Strom3, Martin Fassnacht3. 1. Department of Internal Medicine IEndocrine and Diabetes Unit, University Hospital, University of Wuerzburg, Oberduerrbacherstrasse 6, 97080 Wuerzburg, GermanyEndocrinology and Diabetology UnitDepartment of Clinical Sciences and Community Health, University of Milan, Milan, ItalyCentral LaboratoryUniversity Hospital, University of Wuerzburg, Wuerzburg, GermanyInstitute of Human GeneticsHelmholtz Zentrum Munich, Neuherberg, GermanyComprehensive Cancer Center MainfrankenUniversity of Wuerzburg, Wuerzburg, GermanyMedizinische Klinik and Poliklinik IVLudwig-Maximilians University, Munich, GermanyCore Unit Systems MedicineUniversity of Wuerzburg, Wuerzburg, GermanyEndocrinology UnitDepartment of Biomedical Sciences, Humanitas Research Hospital, Humanitas University, Rozzano, Milan, ItalyInstitute of Pharmacology and Toxicology and Bioimaging CenterUniversity of Wuerzburg, Wuerzburg, GermanyDepartment of NeurosurgeryUniversity Hospital of Erlangen, Erlangen, GermanyNeurosurgeryUniversity Hospital of Hamburg-Eppendorf, Hamburg, GermanyInstitute of Human GeneticsTechnische Universitaet Muenchen, Munich, Germany Ronchi_C@ukw.de. 2. Department of Internal Medicine IEndocrine and Diabetes Unit, University Hospital, University of Wuerzburg, Oberduerrbacherstrasse 6, 97080 Wuerzburg, GermanyEndocrinology and Diabetology UnitDepartment of Clinical Sciences and Community Health, University of Milan, Milan, ItalyCentral LaboratoryUniversity Hospital, University of Wuerzburg, Wuerzburg, GermanyInstitute of Human GeneticsHelmholtz Zentrum Munich, Neuherberg, GermanyComprehensive Cancer Center MainfrankenUniversity of Wuerzburg, Wuerzburg, GermanyMedizinische Klinik and Poliklinik IVLudwig-Maximilians University, Munich, GermanyCore Unit Systems MedicineUniversity of Wuerzburg, Wuerzburg, GermanyEndocrinology UnitDepartment of Biomedical Sciences, Humanitas Research Hospital, Humanitas University, Rozzano, Milan, ItalyInstitute of Pharmacology and Toxicology and Bioimaging CenterUniversity of Wuerzburg, Wuerzburg, GermanyDepartment of NeurosurgeryUniversity Hospital of Erlangen, Erlangen, GermanyNeurosurgeryUniversity Hospital of Hamburg-Eppendorf, Hamburg, GermanyInstitute of Human GeneticsTechnische Universitaet Muenchen, Munich, Germany. 3. Department of Internal Medicine IEndocrine and Diabetes Unit, University Hospital, University of Wuerzburg, Oberduerrbacherstrasse 6, 97080 Wuerzburg, GermanyEndocrinology and Diabetology UnitDepartment of Clinical Sciences and Community Health, University of Milan, Milan, ItalyCentral LaboratoryUniversity Hospital, University of Wuerzburg, Wuerzburg, GermanyInstitute of Human GeneticsHelmholtz Zentrum Munich, Neuherberg, GermanyComprehensive Cancer Center MainfrankenUniversity of Wuerzburg, Wuerzburg, GermanyMedizinische Klinik and Poliklinik IVLudwig-Maximilians University, Munich, GermanyCore Unit Systems MedicineUniversity of Wuerzburg, Wuerzburg, GermanyEndocrinology UnitDepartment of Biomedical Sciences, Humanitas Research Hospital, Humanitas University, Rozzano, Milan, ItalyInstitute of Pharmacology and Toxicology and Bioimaging CenterUniversity of Wuerzburg, Wuerzburg, GermanyDepartment of NeurosurgeryUniversity Hospital of Erlangen, Erlangen, GermanyNeurosurgeryUniversity Hospital of Hamburg-Eppendorf, Hamburg, GermanyInstitute of Human GeneticsTechnische Universitaet Muenchen, Munich, Germany Department of Internal Medicine IEndocrine and Diabetes Unit, University Hospital, University of Wuerzburg, Oberduerrbacherstrasse 6, 97080 Wuerzburg, GermanyEndocrinology and Diabetology UnitDepartment of Clinical Sciences and Community Health, University of Milan, Milan, ItalyCentral LaboratoryUniversity Hospital, University of Wuerzburg, Wuerzburg, GermanyInstitute of Human GeneticsHelmholtz Zentrum Munich, Neuherberg, GermanyComprehensive Cancer Center MainfrankenUniversity of Wuerzburg, Wuerzburg, GermanyMedizinische Klinik and Poliklinik IVLudwig-Maximilians University, Munich, GermanyCore Unit Systems MedicineUniversity of Wuerzburg, Wuerzburg, GermanyEndocrinology UnitDepartment of Biomedical Sciences, Humanitas Research Hospital, Humanitas University, Rozzano, Milan, ItalyInstitute of Pharmacology and Toxicology and Bioimaging CenterUniversity of Wuerzburg, W
Abstract
CONTEXT: Alterations in the cAMP signaling 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 five cases (16.1%), while no somatic mutations were observed in both PRKACA and USP8. Whole-exome sequencing identified 132 protein-altering somatic mutations in 31/36 tumors with a median of three mutations per sample (range: 1-13). The only recurrent mutations have been observed in GNAS (31.4% of cases). However, seven genes involved in cAMP signaling pathway were affected in 14 of 36 samples and eight 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 significant correlation between genetic alterations and the clinical data was observed. CONCLUSION: 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 signaling might be involved in the pathogenesis of these tumors.
CONTEXT: Alterations in the cAMP signaling 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 five cases (16.1%), while no somatic mutations were observed in both PRKACA and USP8. Whole-exome sequencing identified 132 protein-altering somatic mutations in 31/36 tumors with a median of three mutations per sample (range: 1-13). The only recurrent mutations have been observed in GNAS (31.4% of cases). However, seven genes involved in cAMP signaling pathway were affected in 14 of 36 samples and eight 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 significant correlation between genetic alterations and the clinical data was observed. CONCLUSION: 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 signaling might be involved in the pathogenesis of these tumors.
Authors: Wenya Linda Bi; Peleg Horowitz; Noah F Greenwald; Malak Abedalthagafi; Pankaj K Agarwalla; Wiliam J Gibson; Yu Mei; Steven E Schumacher; Uri Ben-David; Aaron Chevalier; Scott Carter; Grace Tiao; Priscilla K Brastianos; Azra H Ligon; Matthew Ducar; Laura MacConaill; Edward R Laws; Sandro Santagata; Rameen Beroukhim; Ian F Dunn Journal: Clin Cancer Res Date: 2016-10-05 Impact factor: 12.531
Authors: Wenya Linda Bi; Noah F Greenwald; Shakti H Ramkissoon; Malak Abedalthagafi; Shannon M Coy; Keith L Ligon; Yu Mei; Laura MacConaill; Matt Ducar; Le Min; Sandro Santagata; Ursula B Kaiser; Rameen Beroukhim; Edward R Laws; Ian F Dunn Journal: Endocrinology Date: 2017-07-01 Impact factor: 4.736
Authors: Scott Haston; Sara Pozzi; Gabriela Carreno; Saba Manshaei; Leonidas Panousopoulos; Jose Mario Gonzalez-Meljem; John R Apps; Alex Virasami; Selvam Thavaraj; Alice Gutteridge; Tim Forshew; Richard Marais; Sebastian Brandner; Thomas S Jacques; Cynthia L Andoniadou; Juan Pedro Martinez-Barbera Journal: Development Date: 2017-05-15 Impact factor: 6.868