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Germline MET pathogenic variants in papillary renal cell carcinomas type I: specific phenotype in French population and novel germline pathogenic variant MET c.3389T>C, p.(Leu1130Ser)
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  • Molka SEBAI,
  • David TULASNE,
  • Sandrine Caputo,
  • Virginie VERKARRE ,
  • Marie FERNANDES ,
  • Fanny REINHART,
  • Severine 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
Molka SEBAI
Department of Medical Biology and Pathology, Cancer Genetics Laboratory, Gustave Roussy, 94800
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David TULASNE
Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000
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Sandrine Caputo
Department of Genetics, Institut Curie, 75005
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Virginie VERKARRE
Department of Pathology, Georges Pompidou European Hospital, Assistance Publique Hôpitaux de Paris, 75015
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Marie FERNANDES
Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000
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Fanny REINHART
Department of Pathology, Georges Pompidou European Hospital, Assistance Publique Hôpitaux de Paris, 75015
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Severine ADAMS
Department of Medical Biology and Pathology, Cancer Genetics Laboratory, Gustave Roussy, 94800
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Christine Maugard
Department of molecular oncogenetics, Hôpitaux Universitaires de Strasbourg, 67091
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Olivier Caron
Department of Medical Oncogenetics, Gustave Roussy, 94800
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Marine GUILLAUD-BATAILLE
Department of Medical Biology and Pathology, Cancer Genetics Laboratory, Gustave Roussy, 94800
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Pascaline  BERTHET
French National Network for Rare Cancers in Adults PREDIR labelled by INCa, AP-HP, Hôpital Bicêtre, 94270
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Yves-Jean Bignon
French National Network for Rare Cancers in Adults PREDIR labelled by INCa, AP-HP, Hôpital Bicêtre, 94270
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Brigitte Bressac-de Paillerets
Department of Medical Biology and Pathology, Cancer Genetics Laboratory, Gustave Roussy, 94800
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Nelly BURNICHON
Université de Paris, AP-HP, Hôpital Européen Georges Pompidou, Genetics department
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Jean Chiesa
Department of Cytogenetics, Nimes University Hospital, 30029
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Sophie Giraud
Genetics Department, Hospices Civils de LYON (HCL), 69002
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Sophie LEJEUNE
Department of genetics, CHRU Lille, 59000
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Jean-Marc LIMACHER
Genetics Department, Hôpitaux civils de Colmar, 68024
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Antoine de Pauw
Department of Genetics, Institut Curie, 75005
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Dominique Stoppa-Lyonnet
Department of Genetics, Institut Curie, 75005
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Hélène ZATTARA-CANNONI
Department of Genetics, Hôpital de la Timone Enfants, 13005
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Sophie DEVEAUX
French National Network for Rare Cancers in Adults PREDIR labelled by INCa, AP-HP, Hôpital Bicêtre, 94270
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Rosette LIDEREAU
Department of Genetics, Institut Curie, 75005
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Stéphane RICHARD
French National Network for Rare Cancers in Adults PREDIR labelled by INCa, AP-HP, Hôpital Bicêtre, 94270
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Etienne Rouleau
Department of Medical Biology and Pathology, Cancer Genetics Laboratory, Gustave Roussy, 94800
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Abstract

Hereditary papillary renal cell carcinoma (HPRCC) 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 HPRCC families. We reviewed the medical and molecular records of a large French series of 158 patients screened for MET oncogenic variants (153 index-cases and five relatives). MET pathogenic variant rate was 10.4% (16/153) with 37.5% among patients with familial PRCC1 and 3.3% among patients with sporadic PRCC1 presentation. The phenotype in MET mutated cases was characteristic as PRCC1 tumors were mainly bilateral (82.3%) and multifocal (85.8%). Histologically, six out of seven patients with MET germline pathogenic variant harboured biphasic squamoid alveolar PRCC. Genetic screening identified in four index-cases a novel missense pathogenic variant within the tyrosine kinase domain: MET c.3389T>C, p.(Leu1130Ser). Functional assay confirmed its oncogenic effect with a constitutive phosphorylation of ERK protein and an abnormal focus formation induced. 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.

Peer review status:UNDER REVIEW

24 May 2021Submitted to Human Mutation
25 May 2021Assigned to Editor
25 May 2021Submission Checks Completed
02 Jun 2021Reviewer(s) Assigned