Making sense of giant cell lesions of the jaws (GCLJ): lessons learned from next‐generation sequencing

Abstract

Next-generation sequencing has revealed mutations in several bone-related lesions and was recently used to uncover the genetic basis of giant cell lesions of the jaws (GCLJ). Consistent with their benign nature, GCLJ show a low tumor mutation burden. They also harbor somatic, heterozygous, mutually exclusive mutations in TRPV4, KRAS, or FGFR1. These signature mutations occur only in a subset of lesional cells, suggesting the existence of a 'landscaping effect', with mutant cells inducing abnormal accumulation of non-mutant cells that form the tumor mass. Osteoclast-rich lesions with histological similarities to GCLJ can occur in the jaws sporadically or in association with genetically inherited syndromes. Based on recent results, the pathogenesis of a subgroup of sporadic GCLJ seems closely related to non-ossifying fibroma of long bones, with both lesions sharing MAPK pathway-activating mutations. In this review, we extrapolate from these recent findings to contextualize GCLJ genetics and we highlight the therapeutic implications of this new information.

KRAS mutations in brown tumor of the jaws in hyperparathyroidism

“…Recently, KRAS , TRPV4, and FGFR1 gain‐of‐function mutations were reported by our group in central and peripheral giant cell lesions of the jaws 8 . Following this work, KRAS and FGFR1 mutations have been shown to also occur in non‐ossifying fibromas of bones, 9 reinforcing the speculation that these lesions might represent the same entity 10‐12 . KRAS mutations have also been reported in implant‐associated peripheral giant cell granuloma 13 .…”

“…Giant cell lesions of the jaws occur in genetic syndromes caused by RAS mutations, such as Noonan syndrome, cardio‐facio‐cutaneous syndrome, Leopard syndrome, oculoectodermal syndrome, and Schimmelpenning syndrome (reviewed by ref. 12 ). Additionally, these lesions can occur in osteoglophonic dysplasia, which results from FGFR1 mutations 12,14 .…”

“… 12 ). Additionally, these lesions can occur in osteoglophonic dysplasia, which results from FGFR1 mutations 12,14 . Recently, somatic heterozygous KRAS , FGFR1, and TRPV4 pathogenic mutations have been reported in sporadic giant cell lesions of the jaws 8 .…”

“…In addition, genetic syndromes caused by RAS and FGFR1 mutations may show giant cell lesions of the jaws as a component (reviewed by ref. 12 ). Therefore, the present study aimed to investigate if KRAS , TRPV4, and FGFR1 mutations also occur in brown tumor of hyperparathyroidism.…”

Central giant cell granuloma of the maxilla: Long‐term follow‐up of a patient treated with an adjuvant corticosteroid

“…1,31,32 Importantly, studies have unveiled that the pathogenesis of a subgroup of CGCG seems to be closely related to the pathogenesis of nonossifying fibroma of long bones, as both lesions share MAPK pathway-activating mutations. 33 Immunohistochemistry using calcitonin and glucocorticoid receptors as a tool for choosing the optimal treatment in cases of CGCG has been widely reported in the literature. [9][10][11] Nogueira et al 10 suggested that CGCG with a good response to glucocorticoids may have a median Hscore of 142 for glucocorticoids in the mononuclear component and of 48 in the multinucleated giant cells.…”