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

Author

Listed:
  • Carolina Cavalieri Gomes

    (McGill University
    Universidade Federal de Minas Gerais)

  • Tenzin Gayden

    (McGill University)

  • Andrea Bajic

    (McGill University)

  • Osama F. Harraz

    (University of Vermont)

  • Jonathan Pratt

    (McGill University)

  • Hamid Nikbakht

    (McGill University
    McGill University and Genome Quebec Innovation Centre)

  • Eric Bareke

    (McGill University
    McGill University and Genome Quebec Innovation Centre)

  • 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
    University of Montreal)

  • HyeRim Han

    (Jewish General Hospital)

  • Barbara Rivera

    (Jewish General Hospital
    McGill University)

  • Leonie G. Mikael

    (McGill University and McGill University Heath Centre Research Institute)

  • Nicolas Jay

    (McGill University)

  • Claudia L. Kleinman

    (McGill University
    Jewish General Hospital)

  • Elvis Terci Valera

    (McGill University
    Universidade de São Paulo)

  • Angelia V. Bassenden

    (McGill University)

  • Albert M. Berghuis
  • Jacek Majewski

    (McGill University
    McGill University and Genome Quebec Innovation Centre)

  • Mark T. Nelson

    (University of Vermont
    University of Manchester)

  • Ricardo Santiago Gomez

    (McGill University
    Universidade Federal de Minas Gerais)

  • Nada Jabado

    (McGill University
    McGill University and McGill University Heath Centre Research Institute)

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.

Suggested Citation

  • 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 S, 2018. "TRPV4 and KRAS and FGFR1 gain-of-function mutations drive giant cell lesions of the jaw," Nature Communications, Nature, vol. 9(1), pages 1-8, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06690-4
    DOI: 10.1038/s41467-018-06690-4
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