Letícia Martins Guimarães1, Isadora Pereira Gomes1, Thaís Dos Santos Fontes Pereira1, Bruno Augusto Benevenuto de Andrade2, Mário José Romañach2, Júlio César Tanos de Lacerda3, Hélder Antônio Rebelo Pontes4, Peter A Brennan5, Siavash Rahimi6,7, Román Carlos8, Adalberto Mosqueda-Taylor9, Ronell Bologna-Molina10, Fabricio Passador-Santos11, Ricardo Santiago Gomez1, Carolina Cavaliéri Gomes12. 1. Department of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil. 2. Department of Oral Diagnosis and Pathology, School of Dentistry, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil. 3. Stomatology Service of Hospital Odilon Behrens, Belo Horizonte, Brazil. 4. Service of Oral Pathology, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará (UFPA), Belém, Brazil. 5. Department of Oral and Maxillofacial Surgery, Queen Alexandra Hospital, Portsmouth, UK. 6. School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK. 7. Frontier Pathology-Royal Sussex County Hospital, Brighton, UK. 8. Centro Clinico de Cabeza y Cuello, Guatemala City, Guatemala. 9. Health Care Department, Universidad Autónoma Metropolitana, Xochimilco, Mexico. 10. Molecular Pathology Area, School of Dentistry, Universidad de la República (UDELAR), Montevideo, Uruguay. 11. Oral Pathology, São Leopoldo Mandic Institute and Research Center, Campinas, Brazil. 12. Department of Pathology, Institute of Biological Science, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
Abstract
BACKGROUND: Brown tumors are giant cell-rich lesions that result from abnormal bone metabolism in hyperparathyroidism, one of the most common endocrine disorders worldwide. Brown tumors occasionally affect the jaws and, despite well-known clinical and microscopic features, their molecular pathogenesis remains unclear. We investigated the presence of pathogenic activating mutations in TRPV4, FGFR1, and KRAS in a cohort of brown tumors since these have recently been reported in giant-cell lesions of the jaws and non-ossifying fibromas of the bones (FGFR1 and KRAS), which are histologic mimics of brown tumors. METHODS: We target sequenced 13 brown tumors of the jaws associated with primary or secondary hyperparathyroidism. As mutations in these genes are known to activate the MAPK/ERK signaling pathway, we also assessed the immunostaining of the phosphorylated form of ERK1/2 (pERK1/2) in these lesions. RESULTS: KRAS pathogenic mutations were detected in seven cases (p.G12V n = 4, p.G12D n = 1, p.G13D n = 1, p.A146T n = 1). KRAS variants of unknown significance (VUS), p.A134T and p.E37K, were also detected. All samples showed wild-type sequences for FGFR1 and TRPV4 genes. The activation of the MAPK/ERK signaling pathway was demonstrated by pERK1/2 immunohistochemical positivity of the brown tumors´ mononuclear cells. CONCLUSION: Mutations in KRAS and activation of the MAPK/ERK signaling pathway were detected in brown tumors of hyperparathyroidism of the jaws, expanding the spectrum of giant cell lesions whose molecular pathogenesis involve RAS signaling.
BACKGROUND: Brown tumors are giant cell-rich lesions that result from abnormal bone metabolism in hyperparathyroidism, one of the most common endocrine disorders worldwide. Brown tumors occasionally affect the jaws and, despite well-known clinical and microscopic features, their molecular pathogenesis remains unclear. We investigated the presence of pathogenic activating mutations in TRPV4, FGFR1, and KRAS in a cohort of brown tumors since these have recently been reported in giant-cell lesions of the jaws and non-ossifying fibromas of the bones (FGFR1 and KRAS), which are histologic mimics of brown tumors. METHODS: We target sequenced 13 brown tumors of the jaws associated with primary or secondary hyperparathyroidism. As mutations in these genes are known to activate the MAPK/ERK signaling pathway, we also assessed the immunostaining of the phosphorylated form of ERK1/2 (pERK1/2) in these lesions. RESULTS: KRAS pathogenic mutations were detected in seven cases (p.G12V n = 4, p.G12D n = 1, p.G13D n = 1, p.A146T n = 1). KRAS variants of unknown significance (VUS), p.A134T and p.E37K, were also detected. All samples showed wild-type sequences for FGFR1 and TRPV4 genes. The activation of the MAPK/ERK signaling pathway was demonstrated by pERK1/2 immunohistochemical positivity of the brown tumors´ mononuclear cells. CONCLUSION: Mutations in KRAS and activation of the MAPK/ERK signaling pathway were detected in brown tumors of hyperparathyroidism of the jaws, expanding the spectrum of giant cell lesions whose molecular pathogenesis involve RAS signaling.