Anne-Lise Lecoq1, Jérôme Bouligand1, Mirella Hage1, Laure Cazabat2, Sylvie Salenave2, Agnès Linglart3, Jacques Young1, Anne Guiochon-Mantel1, Philippe Chanson1, Peter Kamenický4. 1. Faculté de Médecine Paris-SudUniversité Paris-Sud, Université Paris-Saclay, UMR-S1185, 94276 Le Kremlin Bicêtre, FranceAssistance Publique-Hôpitaux de ParisHôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, 94275 Le Kremlin-Bicêtre, FranceService de Génétique moléculairePharmacogénétique et Hormonologie, 94275 Le Kremlin-Bicêtre, FranceService d'Endocrinologie Pédiatrique94275 Le Kremlin-Bicêtre, FranceInstitut National de la Santé et de la Recherche Médicale (INSERM) U118594276 Le Kremlin-Bicêtre, France Faculté de Médecine Paris-SudUniversité Paris-Sud, Université Paris-Saclay, UMR-S1185, 94276 Le Kremlin Bicêtre, FranceAssistance Publique-Hôpitaux de ParisHôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, 94275 Le Kremlin-Bicêtre, FranceService de Génétique moléculairePharmacogénétique et Hormonologie, 94275 Le Kremlin-Bicêtre, FranceService d'Endocrinologie Pédiatrique94275 Le Kremlin-Bicêtre, FranceInstitut National de la Santé et de la Recherche Médicale (INSERM) U118594276 Le Kremlin-Bicêtre, France Faculté de Médecine Paris-SudUniversité Paris-Sud, Université Paris-Saclay, UMR-S1185, 94276 Le Kremlin Bicêtre, FranceAssistance Publique-Hôpitaux de ParisHôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, 94275 Le Kremlin-Bicêtre, FranceService de Génétique moléculairePharmacogénétique et Hormonologie, 94275 Le Kremlin-Bicêtre, FranceService d'Endocrinologie Pédiatrique94275 Le Kremlin-Bicêtre, FranceInstitut National de la Santé et de la Recherche Médicale (INSERM) U118594276 Le Kremlin-Bicêtre, France. 2. Faculté de Médecine Paris-SudUniversité Paris-Sud, Université Paris-Saclay, UMR-S1185, 94276 Le Kremlin Bicêtre, FranceAssistance Publique-Hôpitaux de ParisHôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, 94275 Le Kremlin-Bicêtre, FranceService de Génétique moléculairePharmacogénétique et Hormonologie, 94275 Le Kremlin-Bicêtre, FranceService d'Endocrinologie Pédiatrique94275 Le Kremlin-Bicêtre, FranceInstitut National de la Santé et de la Recherche Médicale (INSERM) U118594276 Le Kremlin-Bicêtre, France. 3. Faculté de Médecine Paris-SudUniversité Paris-Sud, Université Paris-Saclay, UMR-S1185, 94276 Le Kremlin Bicêtre, FranceAssistance Publique-Hôpitaux de ParisHôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, 94275 Le Kremlin-Bicêtre, FranceService de Génétique moléculairePharmacogénétique et Hormonologie, 94275 Le Kremlin-Bicêtre, FranceService d'Endocrinologie Pédiatrique94275 Le Kremlin-Bicêtre, FranceInstitut National de la Santé et de la Recherche Médicale (INSERM) U118594276 Le Kremlin-Bicêtre, France Faculté de Médecine Paris-SudUniversité Paris-Sud, Université Paris-Saclay, UMR-S1185, 94276 Le Kremlin Bicêtre, FranceAssistance Publique-Hôpitaux de ParisHôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, 94275 Le Kremlin-Bicêtre, FranceService de Génétique moléculairePharmacogénétique et Hormonologie, 94275 Le Kremlin-Bicêtre, FranceService d'Endocrinologie Pédiatrique94275 Le Kremlin-Bicêtre, FranceInstitut National de la Santé et de la Recherche Médicale (INSERM) U118594276 Le Kremlin-Bicêtre, France. 4. Faculté de Médecine Paris-SudUniversité Paris-Sud, Université Paris-Saclay, UMR-S1185, 94276 Le Kremlin Bicêtre, FranceAssistance Publique-Hôpitaux de ParisHôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, 94275 Le Kremlin-Bicêtre, FranceService de Génétique moléculairePharmacogénétique et Hormonologie, 94275 Le Kremlin-Bicêtre, FranceService d'Endocrinologie Pédiatrique94275 Le Kremlin-Bicêtre, FranceInstitut National de la Santé et de la Recherche Médicale (INSERM) U118594276 Le Kremlin-Bicêtre, France Faculté de Médecine Paris-SudUniversité Paris-Sud, Université Paris-Saclay, UMR-S1185, 94276 Le Kremlin Bicêtre, FranceAssistance Publique-Hôpitaux de ParisHôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, 94275 Le Kremlin-Bicêtre, FranceService de Génétique moléculairePharmacogénétique et Hormonologie, 94275 Le Kremlin-Bicêtre, FranceService d'Endocrinologie Pédiatrique94275 Le Kremlin-Bicêtre, FranceInstitut National de la Santé et de la Recherche Médicale (INSERM) U118594276 Le Kremlin-Bicêtre, France Faculté de Médecine Paris-SudUniversité Paris-Sud, Université Paris-Saclay, UMR-S1185, 94276 Le Kremlin Bicêtre, FranceAssistance Publique-Hôpitaux de ParisHôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, 94275 Le Kremlin-Bicêtre, FranceService de Génétique moléculairePharmacogénétique et Hormonologie, 94275 Le Kremlin-Bicêtre, FranceService d'Endocrinologie Pédiatrique94275 Le Kremlin-Bicêtre, FranceInstitut National de la Santé et de la Recherche Médicale (INSERM) U118594276 Le Kremlin-Bicêtre, France peter.kamenicky@u-psud.fr.
Abstract
CONTEXT: Recently, germline and somatic GPR101 p.(E308D) mutation was found in patients with isolated acromegaly. It is not known whether GPR101 point mutations are associated with other histological types of pituitary adenoma. OBJECTIVE: We sought germline GPR101 mutations in patients with sporadic pituitary adenomas, and compared the phenotypes of GPR101 mutation carriers and AIP mutation carriers. DESIGN: An observational cohort study performed between 2007 and 2014 in a single referral center. PARTICIPANTS: This prospective study involved 766 unselected patients (413 women) with sporadic pituitary adenomas of all histotypes. METHODS: Entire GPR101 and AIP coding sequence were screened for germline mutations. RESULTS: Twelve patients (1.6%) were found to carry the GPR101 p.(E308D) mutation or rare GPR101 variants. The minor allele frequency of the GPR101 mutation and variants was higher in patients with pituitary adenomas than in unaffected individuals included in the Exome Aggregation Consortium database. Three of the six patients with the GPR101 p.(E308D) mutation had adult-onset acromegaly, two had adrenocorticotropin-secreting adenomas, and one had a nonfunctioning macroadenoma. Six patients carried rare GPR101 variants. Germline AIP mutations or rare AIP variants were identified in 32 patients (4.2%). AIP mutation carriers were younger at diagnosis than GPR101 mutation carriers and non carriers. None of the patients harbored mutations in both the GPR101 and AIP genes. CONCLUSION: Germline GPR101 mutations are very rare in patients with sporadic pituitary adenomas of various histotypes. No digenism with AIP was identified. Further studies are required to establish whether and how genetic variation in GPR101 gene contributes to pituitary tumorigenesis.
CONTEXT: Recently, germline and somatic GPR101 p.(E308D) mutation was found in patients with isolated acromegaly. It is not known whether GPR101 point mutations are associated with other histological types of pituitary adenoma. OBJECTIVE: We sought germline GPR101 mutations in patients with sporadic pituitary adenomas, and compared the phenotypes of GPR101 mutation carriers and AIP mutation carriers. DESIGN: An observational cohort study performed between 2007 and 2014 in a single referral center. PARTICIPANTS: This prospective study involved 766 unselected patients (413 women) with sporadic pituitary adenomas of all histotypes. METHODS: Entire GPR101 and AIP coding sequence were screened for germline mutations. RESULTS: Twelve patients (1.6%) were found to carry the GPR101 p.(E308D) mutation or rare GPR101 variants. The minor allele frequency of the GPR101 mutation and variants was higher in patients with pituitary adenomas than in unaffected individuals included in the Exome Aggregation Consortium database. Three of the six patients with the GPR101 p.(E308D) mutation had adult-onset acromegaly, two had adrenocorticotropin-secreting adenomas, and one had a nonfunctioning macroadenoma. Six patients carried rare GPR101 variants. Germline AIP mutations or rare AIP variants were identified in 32 patients (4.2%). AIP mutation carriers were younger at diagnosis than GPR101 mutation carriers and non carriers. None of the patients harbored mutations in both the GPR101 and AIP genes. CONCLUSION: Germline GPR101 mutations are very rare in patients with sporadic pituitary adenomas of various histotypes. No digenism with AIP was identified. Further studies are required to establish whether and how genetic variation in GPR101 gene contributes to pituitary tumorigenesis.
Authors: Donato Iacovazzo; Richard Caswell; Benjamin Bunce; Sian Jose; Bo Yuan; Laura C Hernández-Ramírez; Sonal Kapur; Francisca Caimari; Jane Evanson; Francesco Ferraù; Mary N Dang; Plamena Gabrovska; Sarah J Larkin; Olaf Ansorge; Celia Rodd; Mary L Vance; Claudia Ramírez-Renteria; Moisés Mercado; Anthony P Goldstone; Michael Buchfelder; Christine P Burren; Alper Gurlek; Pinaki Dutta; Catherine S Choong; Timothy Cheetham; Giampaolo Trivellin; Constantine A Stratakis; Maria-Beatriz Lopes; Ashley B Grossman; Jacqueline Trouillas; James R Lupski; Sian Ellard; Julian R Sampson; Federico Roncaroli; Márta Korbonits Journal: Acta Neuropathol Commun Date: 2016-06-01 Impact factor: 7.801
Authors: Adrian F Daly; David A Cano; Eva Venegas-Moreno; Patrick Petrossians; Elena Dios; Emilie Castermans; Alvaro Flores-Martínez; Vincent Bours; Albert Beckers; Alfonso Soto-Moreno Journal: Endocr Connect Date: 2019-04 Impact factor: 3.335
Authors: Medard F M van den Broek; Bernadette P M van Nesselrooij; Annemarie A Verrijn Stuart; Rachel S van Leeuwaarde; Gerlof D Valk Journal: Front Endocrinol (Lausanne) Date: 2019-12-10 Impact factor: 5.555