Integrated proteomics, phosphoproteomics and metabolomics analyses reveal similarities among giant cell granulomas of the jaws with different genetic mutations

Abstract

Background: Giant cell granuloma of the jaws are benign osteolytic lesions of the jaws. These lesions are genetically characterized by mutually exclusive somatic mutations at TRPV4, KRAS, and FGFR1, and a fourth molecular subgroup which is wild-type for the three mutations. Irrespective of the molecular background, giant cell granulomas show MAPK/ERK activation. However, it remains unclear if these mutations lead to differences in their molecular signaling in giant cell granulomas.Methods: Metabolomics, proteomics, and phosphoproteomics analyses were carried out in formalin-fixed paraffin-embedded samples of giant cell granuloma of the jaws.The study cohort consisted of five lesions harboring mutations in FGFR1, six in KRAS, five in TRPV4, and five that were wild-type for these mutations.Results: Lesions harboring KRAS or FGFR1 mutations showed overall similar proteomics and metabolomics profiles. In all four groups, metabolic pathways showed similarity in apoptosis, cell signaling, gene expression, cell differentiation, and erythrocyte activity. Lesions harboring TRPV4 mutations showed a greater number of enriched pathways related to tissue architecture. On the other hand, the wild-type group presented increased number of enriched pathways related to protein metabolism compared to the other groups. Conclusion:Despite some minor differences, our results revealed an overall similar molecular profile among the groups with different mutational profile at the metabolic, proteic, and phosphopeptidic levels.

Molecular and immunohistochemical testing of bone tumours: review and update

“…Over 80% of nonossifying fibromas harbour recurrent activating alterations in the MAP kinase pathway, including mutually exclusive mutations in KRAS , FGFR1 , and NF1 115 . This is reminiscent of giant cell lesions of the jaw, which harbour recurrent KRAS , FGFR1 , and TRPV4 mutations 116,117 . Recurrent KRAS mutations have also been detected in brown tumours, 118 which are giant cell‐rich lesions arising in the setting of hyperparathyroidism, suggesting that the MAP kinase pathway activation underlies the pathogenesis of multiple giant cell‐rich lesions.…”