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

Carolina Cavaliéri Gomes ,Wagner Henriques Castro,Marina Gonçalves Diniz,Andrea Bajic,Hyerim Han,Mark T Nelson,Nicolas Jay ,Bárbara Rivera ,Hamid Nikbakht,Leonie G Mikael,Angelia V Bassenden,Jonathan Pratt,Osama F Harraz,Ricardo Santiago Gomez,Claudia L Kleinman,Jacek Majewski,Tenzin Gayden,Elvis Terci Valera,Eric Bareke,Daniel Sinnett,A.m Berghuis ,Pascal St-Onge,Nada Jabado

doi:10.1038/s41467-018-06690-4

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.

Highlights

Giant cell lesions of the jaw (GCLJ) are debilitating tumors of unknown origin with limited available therapies
Sequencing results showed that recurrent, heterozygous, mutations in transient receptor potential vanilloid 4 cation channel (TRPV4), KRAS, and FGFR1 occur in 72.4% (42/58) GCLJ (Fig. 1b, c, Supplementary Figs. 2 and 3, Supplementary Data 1)
Our work provides a genetic landscape for giant cell lesions of the jaw

Summary

Introduction

Giant cell lesions of the jaw (GCLJ) are debilitating tumors of unknown origin with limited available therapies. Aggressive forms of GCLJ show frequent escape from this traditional surgical management and limited response to adjuvant therapies including corticosteroids These are painful, rapidly growing and bone perforating recurrent lesions with major functional impact on the jaw and teeth structure[6,9]. Our data show that recurrent, heterozygous, somatic transient receptor potential vanilloid 4 cation channel (TRPV4) p.M713V and p.M713I, KRAS and FGFR1 mutations are the most relevant genetic alterations at the basis of GCLJ These mutations occur in 72% (42/58) of tumors and converge in their effects on activating the MAPK pathway, including the TRPV4 p.M713V and p.M713I amino acid substitutions, as we show

Methods

Results

Conclusion