Germline mutations in the new E1' cryptic exon of the VHL gene in patients with tumours of von Hippel-Lindau disease spectrum or with paraganglioma.

Autor:	Buffet A; Université de Paris, PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, F-75015, Paris, France alexandre.buffet@inserm.fr., Calsina B; Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain., Flores S; Division of Hematology and Medical Oncology, Department of Medicine, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA., Giraud S; Genetics Department, Hospices Civils de LYON (HCL), University Hospital, East Biology and Pathology Center, B-A3, 59 Bld Pinel, 69677, Bron, France.; Réseau National pour Cancers Rares PREDIR labellisé par l'Institut National contre le Cancer, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France., Lenglet M; École Pratique des Hautes Études, PSL Research University, Paris, France.; L'Institut du Thorax, INSERM, Centre National de la Recherche Scientifique (CNRS), Université de Nantes, Nantes, France., Romanet P; Aix Marseille Univ, APHM, INSERM, MMG, Laboratory of Molecular Biology Hospital La Conception, Marseille, France., Deflorenne E; Université de Paris, PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, F-75015, Paris, France., Aller J; Endocrinology and Nutrition Service. Hospital Universitario Puerta de Hierro, 28222, Majadahonda, Spain., Bourdeau I; Division of Endocrinology, Department of Medicine, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montréal, Quebec, Canada., Bressac-de Paillerets B; Réseau National pour Cancers Rares PREDIR labellisé par l'Institut National contre le Cancer, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France.; Gustave Roussy, Université Paris-Saclay, Département de Biopathologie and INSERM U1186, Villejuif, F-94805, France., Calatayud M; Department of Endocrinology and Nutrition, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain., Dehais C; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Service de Neurologie 2-Mazarin, Paris, France., De Mones Del Pujol E; Service ORL, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France., Elenkova A; Department of Endocrinology, USHATE 'Acad. Ivan Penchev', Medical University Sofia, Sofia, Bulgaria., Herman P; Assistance Publique, Hôpitaux de Paris, Service ORL-CCF, hôpital Lariboisière, université Paris VII, Paris, France., Kamenický P; Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse, Le Kremlin Bicetre, France., Lejeune S; Réseau National pour Cancers Rares PREDIR labellisé par l'Institut National contre le Cancer, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France.; Department of Clinical Genetics, Centre Hospitalier Régional et Universitaire de Lille, Lille, France., Sadoul JL; Service d'Endocrinologie, Hôpital de L'Archet, CHU de Nice, Nice, France., Barlier A; Réseau National pour Cancers Rares PREDIR labellisé par l'Institut National contre le Cancer, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France.; Aix Marseille Univ, APHM, INSERM, MMG, Laboratory of Molecular Biology Hospital La Conception, Marseille, France., Richard S; Réseau National pour Cancers Rares PREDIR labellisé par l'Institut National contre le Cancer, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France.; École Pratique des Hautes Études, PSL Research University, Paris, France.; Génétique Oncologique EPHE, INSERM U1186, Gustave Roussy Cancer Campus, Villejuif, France., Favier J; Université de Paris, PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, F-75015, Paris, France., Burnichon N; Université de Paris, PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, F-75015, Paris, France.; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France., Gardie B; École Pratique des Hautes Études, PSL Research University, Paris, France.; L'Institut du Thorax, INSERM, Centre National de la Recherche Scientifique (CNRS), Université de Nantes, Nantes, France., Dahia PL; Division of Hematology and Medical Oncology, Department of Medicine, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA., Robledo M; Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain., Gimenez-Roqueplo AP; Université de Paris, PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, F-75015, Paris, France.; Réseau National pour Cancers Rares PREDIR labellisé par l'Institut National contre le Cancer, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France.; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France.
Jazyk:	angličtina
Zdroj:	Journal of medical genetics [J Med Genet] 2020 Nov; Vol. 57 (11), pp. 752-759. Date of Electronic Publication: 2020 Jan 29.
DOI:	10.1136/jmedgenet-2019-106519
Abstrakt:	Backgrounds: The incidence of germline mutations in the newly discovered cryptic exon (E1') of VHL gene in patients with von Hippel-Lindau (VHL) disease and in patients with paraganglioma or pheochromocytoma (PPGL) is not currently known. Methods: We studied a large international multicentre cohort of 1167 patients with a previous negative genetic testing. Germline DNA from 75 patients with a single tumour of the VHL spectrum ('Single VHL tumour' cohort), 70 patients with multiple tumours of the VHL spectrum ('Multiple VHL tumours' cohort), 76 patients with a VHL disease as described in the literature ('VHL-like' cohort) and 946 patients with a PPGL were screened for E1' genetic variants. Results: Six different genetic variants in E1' were detected in 12 patients. Two were classified as pathogenic, 3 as variants of unknown significance and 1 as benign. The rs139622356 was found in seven unrelated patients but described in only 16 patients out of the 31 390 of the Genome Aggregation Database (p<0.0001) suggesting that this variant might be either a recurrent mutation or a modifier mutation conferring a risk for the development of tumours and cancers of the VHL spectrum. Conclusions: VHL E1' cryptic exon mutations contribute to 1.32% (1/76) of 'VHL-like' cohort and to 0.11% (1/946) of PPGL cohort and should be screened in patients with clinical suspicion of VHL, and added to panels for Next Generation Sequencing (NGS) diagnostic testing of hereditary PPGL. Our data highlight the importance of studying variants identified in deep intronic sequences, which would have been missed by examining only coding sequences of genes/exomes. These variants will likely be more frequently detected and studied with the upcoming implementation of whole-genome sequencing into clinical practice. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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