作者
Laurence Pacot,Audrey Sabbagh,Pierre Sohier,Djihad Hadjadj,Manuela Ye,Anne Boland,Delphine Bacq‐Daian,Ingrid Laurendeau,Audrey Briand‐Suleau,Jean‐François Deleuze,Raphaël Margueron,Michel Vidaud,S. Ferkal,Béatrice Parfait,Dominique Vidaud,H. Adamski,Clarisse Baumann-Morel,Christine Bellanné,Élodie Biet,Pascal Bousque,Christian L. Brand,X. Balguérie,Pierre Castelnau,Yves Chaix,J Chevrant-Breton,E. Collet,J.-F. Cuny,Pascal Chastagner,Marie-Lorraine Chandeclerc,Emmanuel Cheuret,Pascal Cintas,Hélène Dollfus,Christian Derancourt,Valérie Drouin‐Garraud,M. D’Incan,Hélène De Leersnyder,O. Dereure,Diane Doumar,Nicolás Fabre,Vincenza Ferraro,Jill A. Rosenfeld,Carla Oliveíra,Florence Fellmann,Nathalie Feugier Dominique Gaillard,Alice Goldenberg,Lucie Guyant‐Maréchal,B. Guillot,Jean-Sébastien Guillamo,S. Hadj‐Rabia,Dominique Hamel‐Teillac,Isabelle Kemlin,J.‐P. Lacour,Véronique Laithier,Nathalie Lesavre,Stanislas Lyonnet,Kim Maincent,Sophie Maradeix,L. Machet,E Mansat,Nicolás Meyer,Monique Mozelle,Jean Christophe Moreno Celine Moret,E. Puzenat,Stéphane Pinson,Diana Rodriguez,J.‐F. Stalder,Elisabeth Schweitzer,Claire Thalamas,Alexander Hoischen,Alain Verloès,J Zeller,Éric Pasmant,P. Wolkenstein
摘要
Abstract Background Neurofibromatosis type 1 (NF1) is characterized by the highly variable and unpredictable development of benign peripheral nerve sheath tumours: cutaneous (cNFs), subcutaneous (scNFs) and plexiform (pNFs) neurofibromas. Objectives To identify neurofibroma modifier genes, in order to develop a database of patients with NF1. Methods All patients were phenotypically evaluated by a medical practitioner using a standardized questionnaire and the causal NF1 variant identified. We enrolled 1333 patients with NF1 who were genotyped for > 7 million common variants. Results A genome-wide association case-only study identified a significant association with 9q21.33 in the pNF phenotype in the discovery cohort. Twelve, three and four regions suggestive of association at the P ≤ 1 × 10–6 threshold were identified for pNFs, cNFs and scNFs, respectively. Evidence of replication was observed for 4, 2 and 6 loci, including 168 candidate modifier protein-coding genes. Among the candidate modifier genes, some were implicated in the RAS–mitogen-activated protein kinase pathway, cell-cycle control and myelination. Using an original CRISPR/Cas9-based functional assay, we confirmed GAS1 and SPRED2 as pNF and scNF candidate modifiers, as their inactivation specifically affected NF1-mutant Schwann cell growth. Conclusions Our study may shed new light on the pathogenesis of NF1-associated neurofibromas and will, hopefully, contribute to the development of personalized care for patients with this deleterious and life-threatening condition.