KRAS mutations in implant‐associated peripheral giant cell granuloma

Abstract

Objectives To investigate the molecular pathogenesis of implant‐associated peripheral giant cell granuloma (IA‐PGCG). Methods A convenience sample of 15 IA‐PGCG cases was selected. Hotspot mutations of KRAS, FGFR1, and TRPV4 genes, previously reported in conventional giant cell lesions of the jaws, were investigated by Sanger sequencing. As these mutations could activate MAPK/ERK pathway, the expression of phospho‐ERK1/2 was also evaluated by immunohistochemistry. Results KRAS mutations were detected in 8/15 (53.4%) samples. Similar to conventional peripheral giant cell granuloma, the KRAS mutations most frequently occurred in codon 146 (p.A146V, n = 3), followed by codon 12 (p.G12A and p.G12D, n = 1 each) and codon 14 (p.V14L, n = 1). Variants of unknown significance (VUS) were also detected in two cases, affecting codons 37 (p.E37K) and 127 (p.T127I). All samples showed wild‐type (WT) sequences for FGFR1 and TRPV4 genes. Consistent with MAPK/ERK pathway activation, all mononuclear cells of the lesion showed strong staining for phospho‐ERK1/2 protein in the immunohistochemical analysis. Conclusions KRAS mutations and activation of the MAPK‐ERK signaling pathway occur in IA‐PGCG. This is the first study to demonstrate cancer‐associated gene mutations in a non‐neoplastic reactive condition associated with dental implants.

KRAS mutations in brown tumor of the jaws in hyperparathyroidism

“…Notably, KRAS mutations have been previously identified in other giant cell‐rich tumors, including giant cell tumors of the pancreas and liver 23 and in teno‐synovial giant cell tumor 24 . Recently, our group reported KRAS mutations in giant cell‐rich lesions of the oral cavity, including giant cell lesions of the jaws 8 and dental implant‐associated giant cell lesions of the jaws 13 …”

“…The VUS KRAS p.A134T (rs1565884227) and KRAS p.E37K detected in one sample each have been previously reported as somatic in large intestine cancer and chronic myelomonocytic leukemia (COSMIC, https://cancer.sanger.ac.uk/cosmic), respectively. Additionally, KRAS p.E37K was detected in dental implant‐associated giant cell granuloma 13 …”

“…In the context of malignant neoplasia, KRAS codon 12 mutations correspond to 90% of all KRAS mutations in pancreas, colorectal, and lung carcinomas 15 . Mutations in codons 146 and 13 were described in non‐ossifying fibromas, 9 in giant cell lesions of the jaws 8 and in dental implant‐associated giant cell lesions of the jaws, 13 which are also giant cell‐rich lesions but not associated with systemic alterations. These pathogenic mutations have already been extensively studied, but their functional effects seem to be context and tissue specific 15,25,26 .…”

“…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 . In addition, genetic syndromes caused by RAS and FGFR1 mutations may show giant cell lesions of the jaws as a component (reviewed by ref.…”

Peripheral Giant Cell Granuloma of the Jaws as First Sign of Primary Hyperparathyroidism: A Case Series

“…This wide range and high recurrence rate could be related both to incomplete removal of the lesions along with teeth or implants severely involved in the lesions and probably to the lack of screening of hormonal imbalances after certain histological diagnosis of PGCG is achieved. Histologically, PGCG not associated with PHPT are characterized by an increase of microvessel density and Bcl-2 and CD68 expressions [24] and mutations of KRAS and MAPK [25]. Nevertheless, further studies are necessary in order to understand if these findings are detectable in PGCG associated to PHPT too.…”