TRPV4 and KRAS and FGFR1 gain-of-function mutations drive giant cell lesions of the jaw

Carolina Cavalieri Gomes, Tenzin Gayden, Andrea Bajic, Osama F. Harraz, Jonathan Pratt, Hamid Nikbakht, Eric Bareke, Marina Gonçalves Diniz, Wagner Henriques Castro, Pascal St-Onge, Daniel Sinnett, HyeRim Han, Barbara Rivera, Leonie G. Mikael, Nicolas Jay, Claudia L. Kleinman, Elvis Terci Valera, Angelia V. Bassenden, Albert M. Berghuis, Jacek Majewski, Mark T. Nelson, Ricardo Santiago Gomez () and Nada Jabado ()
Additional contact information
Carolina Cavalieri Gomes: McGill University
Tenzin Gayden: McGill University
Andrea Bajic: McGill University
Osama F. Harraz: University of Vermont
Jonathan Pratt: McGill University
Hamid Nikbakht: McGill University
Eric Bareke: McGill University
Marina Gonçalves Diniz: Universidade Federal de Minas Gerais
Wagner Henriques Castro: Universidade Federal de Minas Gerais
Pascal St-Onge: Université de Montréal
Daniel Sinnett: Université de Montréal
HyeRim Han: Jewish General Hospital
Barbara Rivera: Jewish General Hospital
Leonie G. Mikael: McGill University and McGill University Heath Centre Research Institute
Nicolas Jay: McGill University
Claudia L. Kleinman: McGill University
Elvis Terci Valera: McGill University
Angelia V. Bassenden: McGill University
Jacek Majewski: McGill University
Mark T. Nelson: University of Vermont
Ricardo Santiago Gomez: McGill University
Nada Jabado: McGill University

Nature Communications, 2018, vol. 9, issue 1, 1-8

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06690-4

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