Activating mutations in the MAP‐kinase pathway define non‐ossifying fibroma of bone

Abstract

Non‐ossifying fibroma (NOF), which occasionally results in pathologic fracture, is considered the most common benign and self‐limiting lesion of the growing skeleton. By DNA sequencing we have identified hotspot KRAS, FGFR1 and NF1 mutations in 48 of 59 patients (81.4%) with NOF, at allele frequencies ranging from 0.04 to 0.61. Our findings define NOF as a genetically driven neoplasm caused in most cases by activated MAP‐kinase signalling. Interestingly, this driving force either diminishes over time or at least is not sufficient to prevent autonomous regression and resolution. Beyond its contribution to a better understanding of the molecular pathogenesis of NOF, this study adds another benign lesion to the spectrum of KRAS‐ and MAP‐kinase signalling‐driven tumours. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

MAPK pathway‐activating mutations drive giant cell lesions of the jaws and non‐ossifying fibromas of bone

“…Although TRPV4 p.M713V and p.M713I mutations were exclusive to the central variant of giant cell lesion of the jaw, KRAS and FGFR1 also occurred in the peripheral lesions . Overall, whereas in the study by Baumhoer, Kovac, Sperveslage, Amelin et al 81% (48/59) of non‐ossifying fibromas of bone showed either KRAS , FGFR1 or NF1 mutations , in our study 72% (42/58) of sporadic cases of giant cell lesions of the jaws harboured KRAS , FGFR1 or TRPV4 mutations.…”

“…We read with great interest the study by Baumhoer, Kovac, Sperveslage, Amelin et al . In this paper, the authors searched for pathogenic mutations in 59 patients with non‐ossifying fibroma of bone, reporting KRAS mutations in 38 cases, FGFR1 mutations in eight and NF1 mutations in two cases from patients who were known to have neurofibromatosis type 1 .…”

“…We read with great interest the study by Baumhoer, Kovac, Sperveslage, Amelin et al . In this paper, the authors searched for pathogenic mutations in 59 patients with non‐ossifying fibroma of bone, reporting KRAS mutations in 38 cases, FGFR1 mutations in eight and NF1 mutations in two cases from patients who were known to have neurofibromatosis type 1 . Considering that giant cell lesions of the jaws (also known as oral giant cell granulomas) lack the giant cell tumour of bone H3F3A signature mutations , we have recently investigated the genetic basis of this jaw lesion .…”

“…Whereas non‐ossifying fibroma of bone is a self‐limiting condition that usually shows spontaneous resolution, giant cell lesion of the jaws does not show this indolent course, not even the non‐aggressive forms. It is indeed fascinating that a subgroup of non‐ossifying fibroma of bone and giant cell lesions of the jaws share KRAS and FGFR1 driver mutations, which occur in a mutually exclusive pattern . The KRAS mutations in both lesions occurred in a high proportion in codon 12, and also occurred in other codons, such as 13 and 146 .…”

KRAS mutations in implant‐associated peripheral giant cell granuloma

“…Our research group has recently uncovered somatic heterozygous mutations in KRAS , TRPV4 , and FGFR1 genes in central and conventional PGCG of the jaws (Gomes et al, ). In addition, KRAS and FGFR1 mutations have also been reported in non‐ossifying fibroma of the jaws, another giant cell‐rich lesion that shares histopathological features with IA‐PGCG (Baumhoer et al, ). As the pathogenesis of IA‐PGCG is unclear, we hypothesized that the mutations that occur in conventional giant cell granulomas of the jaws could be the underlining genetic events in the lesions associated with dental implants.…”