Abstract

Giant cell lesions of the jaw (GCLJ) are debilitating tumors of unknown origin with limited available therapies. Here, we analyze 58 sporadic samples using next generation or targeted sequencing and report somatic, heterozygous, gain-of-function mutations in KRAS, FGFR1, and p.M713V/I-TRPV4 in 72% (42/58) of GCLJ. TRPV4 p.M713V/I mutations are exclusive to central GCLJ and occur at a critical position adjacent to the cation permeable pore of the channel. Expression of TRPV4 mutants in HEK293 cells leads to increased cell death, as well as increased constitutive and stimulated channel activity, both of which can be prevented using TRPV4 antagonists. Furthermore, these mutations induce sustained activation of ERK1/2, indicating that their effects converge with that of KRAS and FGFR1 mutations on the activation of the MAPK pathway in GCLJ. Our data extend the spectrum of TRPV4 channelopathies and provide rationale for the use of TRPV4 and RAS/MAPK antagonists at the bedside in GCLJ.

Details

Title
TRPV4 and KRAS and FGFR1 gain-of-function mutations drive giant cell lesions of the jaw
Author
Carolina Cavalieri Gomes 1   VIAFID ORCID Logo  ; Gayden, Tenzin 2   VIAFID ORCID Logo  ; Bajic, Andrea 2   VIAFID ORCID Logo  ; Harraz, Osama F 3   VIAFID ORCID Logo  ; Pratt, Jonathan 2 ; Nikbakht, Hamid 4   VIAFID ORCID Logo  ; Bareke, Eric 4   VIAFID ORCID Logo  ; Marina Gonçalves Diniz 5   VIAFID ORCID Logo  ; Wagner Henriques Castro 5 ; St-Onge, Pascal 6 ; Sinnett, Daniel 7   VIAFID ORCID Logo  ; Han, HyeRim 8 ; Rivera, Barbara 9 ; Mikael, Leonie G 10 ; Nicolas De Jay 2 ; Kleinman, Claudia L 11 ; Valera, Elvis Terci 12   VIAFID ORCID Logo  ; Bassenden, Angelia V 13 ; Berghuis, Albert M 13 ; Majewski, Jacek 4   VIAFID ORCID Logo  ; Nelson, Mark T 14 ; Ricardo Santiago Gomez 15   VIAFID ORCID Logo  ; Jabado, Nada 16   VIAFID ORCID Logo 

1  Department of Human Genetics, McGill University, Montreal, QC, Canada; Department of Pathology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil 
2  Department of Human Genetics, McGill University, Montreal, QC, Canada 
3  Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, VT, USA 
4  Department of Human Genetics, McGill University, Montreal, QC, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada 
5  Department of Oral Surgery and Pathology, Faculty of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil 
6  CHU Sainte-Justine Research Center, Université de Montréal, Montreal, QC, Canada 
7  CHU Sainte-Justine Research Center, Université de Montréal, Montreal, QC, Canada; Department of Pediatrics, University of Montreal, Montreal, QC, Canada 
8  Lady Davis Research Institute, Jewish General Hospital, Montreal, QC, Canada 
9  Lady Davis Research Institute, Jewish General Hospital, Montreal, QC, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada 
10  Department of Pediatrics, McGill University and McGill University Heath Centre Research Institute, Montreal, QC, Canada 
11  Department of Human Genetics, McGill University, Montreal, QC, Canada; Lady Davis Research Institute, Jewish General Hospital, Montreal, QC, Canada 
12  Department of Human Genetics, McGill University, Montreal, QC, Canada; Department of Pediatrics, Ribeirão Preto Medical School, Universidade de São Paulo, São Paulo, Brazil 
13  Department of Biochemistry, McGill University, Montreal, QC, Canada 
14  Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, VT, USA; Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK 
15  Department of Human Genetics, McGill University, Montreal, QC, Canada; Department of Oral Surgery and Pathology, Faculty of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil 
16  Department of Human Genetics, McGill University, Montreal, QC, Canada; Department of Pediatrics, McGill University and McGill University Heath Centre Research Institute, Montreal, QC, Canada 
Pages
1-8
Publication year
2018
Publication date
Nov 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-06690-4
ProQuest document ID
2127936690
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.