Hereditary papillary renal cell carcinoma (HPRC) is a rare inherited renal cancer syndrome characterized by bilateral and multifocal papillary type 1 renal tumors (PRCC1). Activating germline pathogenic variants of MET gene were identified in HPRC families. We reviewed the medical and molecular records of a large French series of 158 patients screened for MET oncogenic variants. MET pathogenic and likely pathogenic variants rate was 12.4% with 40.6% among patients with familial PRCC1 and 5% among patients with sporadic PRCC1. The phenotype in cases with MET pathogenic and likely pathogenic variants was characteristic: PRCC1 tumors were mainly bilateral (84.3%) and multifocal (87.5%). Histologically, six out of seven patients with MET pathogenic variant harboured biphasic squamoid alveolar PRCC. Genetic screening identified one novel pathogenic variant MET c.3389T>C, p.(Leu1130Ser) and three novel likely pathogenic variants: MET c.3257A>T, p.(His1086Leu); MET c.3305T>C, p.(Ile1102Thr) and MET c.3373T>G, p.(Cys1125Gly). Functional assay confirmed their oncogenic effect as they induced an abnormal focus formation. The genotype-phenotype correlation between MET pathogenic variants and PRCC1 presentation should encourage to widen the screening, especially toward non-familial PRCC1. This precise phenotype also constitutes a strong argument for the classification of novel missense variants within the tyrosine kinase domain when functional assays aren't accessible. This article is protected by copyright. All rights reserved.
Human mutation. 2021 Dec 09 [Epub ahead of print]
Molka Sebai, David Tulasne, Sandrine M Caputo, Virginie Verkarre, Marie Fernandes, Fanny Reinhart, Séverine Adams, Christine Maugard, Olivier Caron, Marine Guillaud-Bataille, Pascaline Berthet, Yves-Jean Bignon, Brigitte Bressac-de Paillerets, Nelly Burnichon, Jean Chiesa, Sophie Giraud, Sophie Lejeune, Jean-Marc Limacher, Antoine de Pauw, Dominique Stoppa-Lyonnet, Hélène Zattara-Cannoni, Sophie Deveaux, Rosette Lidereau, Stéphane Richard, Etienne Rouleau
Department of Medical Biology and Pathology, Cancer Genetics Laboratory, Gustave Roussy, 94800, Villejuif, France., Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France., Department of Genetics, Institut Curie, 75005, Paris, France., Department of Pathology, Georges Pompidou European Hospital, Assistance Publique Hôpitaux de Paris, 75015, Paris, France., Department of molecular oncogenetics, Hôpitaux Universitaires de Strasbourg, 67091, Strasbourg, France., Department of Medical Oncogenetics, Gustave Roussy, 94800, Villejuif, France., French National Network for Rare Cancers in Adults PREDIR labelled by INCa, AP-HP, Hôpital Bicêtre, 94270, Le Kremlin-Bicêtre, France., Université de Paris, AP-HP, Hôpital Européen Georges Pompidou, Genetics department, Paris, France., Department of Cytogenetics, Nimes University Hospital, 30029, Nîmes, France., Department of genetics, CHRU Lille, 59000, Lille, France., Genetics Department, Hôpitaux civils de Colmar, 68024, COLMAR, France., Department of Genetics, Hôpital de la Timone Enfants, 13005, Marseille, France.