Profiling of three H3F3A-mutated and denosumab-treated giant cell tumors of bone points to diverging pathways during progression and malignant transformation

Abstract Giant cell tumor of bone (GCTB) is a locally aggressive lesion of intermediate malignancy. Malignant transformation of GCTB is a rare event. In 2013, the humanized monoclonal antibody against receptor activator of nuclear factor-κb-Ligand (RANKL) denosumab was approved for treatment of adva...

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Autores principales:	Marc Hasenfratz, Kevin Mellert, Ralf Marienfeld, Alexandra von Baer, Markus Schultheiss, P. D. Roitman, L. A. Aponte-Tinao, Burkhard Lehner, Peter Möller, Gunhild Mechtersheimer, Thomas F. E. Barth
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7e362e1fc5aa4bdcbb09fa7a3c4adf92
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spelling	oai:doaj.org-article:7e362e1fc5aa4bdcbb09fa7a3c4adf922021-12-02T11:37:18ZProfiling of three H3F3A-mutated and denosumab-treated giant cell tumors of bone points to diverging pathways during progression and malignant transformation10.1038/s41598-021-85319-x2045-2322https://doaj.org/article/7e362e1fc5aa4bdcbb09fa7a3c4adf922021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85319-xhttps://doaj.org/toc/2045-2322Abstract Giant cell tumor of bone (GCTB) is a locally aggressive lesion of intermediate malignancy. Malignant transformation of GCTB is a rare event. In 2013, the humanized monoclonal antibody against receptor activator of nuclear factor-κb-Ligand (RANKL) denosumab was approved for treatment of advanced GCTB. Since then, several reports have questioned the role of denosumab during occasional malignant transformation of GCTB. We report on three patients with H3F3A-mutated GCTBs, treated with denosumab. The tissue samples were analysed by histomorphology, immunohistochemistry, and in two instances by next generation panel sequencing of samples before and after treatment. One patient had a mutation of ARID2 in the recurrence of the GCTB under treatment with denosumab. One patient developed a pleomorphic sarcoma and one an osteoblastic osteosarcoma during treatment. Sequencing revealed a persisting H3F3A mutation in the osteosarcoma while the pleomorphic sarcoma lost the H3F3A mutation; however, a FGFR1 mutation, both in the recurrence and in the pleomorphic sarcoma persisted. In addition, the pleomorphic sarcoma showed an AKT2 and a NRAS mutation. These data are inconclusive concerning the role denosumab plays in the event of malignant progression/transformation of GCTB and point to diverging pathways of tumor progression of GCTB associated with this treatment.Marc HasenfratzKevin MellertRalf MarienfeldAlexandra von BaerMarkus SchultheissP. D. RoitmanL. A. Aponte-TinaoBurkhard LehnerPeter MöllerGunhild MechtersheimerThomas F. E. BarthNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Marc Hasenfratz Kevin Mellert Ralf Marienfeld Alexandra von Baer Markus Schultheiss P. D. Roitman L. A. Aponte-Tinao Burkhard Lehner Peter Möller Gunhild Mechtersheimer Thomas F. E. Barth Profiling of three H3F3A-mutated and denosumab-treated giant cell tumors of bone points to diverging pathways during progression and malignant transformation
description	Abstract Giant cell tumor of bone (GCTB) is a locally aggressive lesion of intermediate malignancy. Malignant transformation of GCTB is a rare event. In 2013, the humanized monoclonal antibody against receptor activator of nuclear factor-κb-Ligand (RANKL) denosumab was approved for treatment of advanced GCTB. Since then, several reports have questioned the role of denosumab during occasional malignant transformation of GCTB. We report on three patients with H3F3A-mutated GCTBs, treated with denosumab. The tissue samples were analysed by histomorphology, immunohistochemistry, and in two instances by next generation panel sequencing of samples before and after treatment. One patient had a mutation of ARID2 in the recurrence of the GCTB under treatment with denosumab. One patient developed a pleomorphic sarcoma and one an osteoblastic osteosarcoma during treatment. Sequencing revealed a persisting H3F3A mutation in the osteosarcoma while the pleomorphic sarcoma lost the H3F3A mutation; however, a FGFR1 mutation, both in the recurrence and in the pleomorphic sarcoma persisted. In addition, the pleomorphic sarcoma showed an AKT2 and a NRAS mutation. These data are inconclusive concerning the role denosumab plays in the event of malignant progression/transformation of GCTB and point to diverging pathways of tumor progression of GCTB associated with this treatment.
format	article
author	Marc Hasenfratz Kevin Mellert Ralf Marienfeld Alexandra von Baer Markus Schultheiss P. D. Roitman L. A. Aponte-Tinao Burkhard Lehner Peter Möller Gunhild Mechtersheimer Thomas F. E. Barth
author_facet	Marc Hasenfratz Kevin Mellert Ralf Marienfeld Alexandra von Baer Markus Schultheiss P. D. Roitman L. A. Aponte-Tinao Burkhard Lehner Peter Möller Gunhild Mechtersheimer Thomas F. E. Barth
author_sort	Marc Hasenfratz
title	Profiling of three H3F3A-mutated and denosumab-treated giant cell tumors of bone points to diverging pathways during progression and malignant transformation
title_short	Profiling of three H3F3A-mutated and denosumab-treated giant cell tumors of bone points to diverging pathways during progression and malignant transformation
title_full	Profiling of three H3F3A-mutated and denosumab-treated giant cell tumors of bone points to diverging pathways during progression and malignant transformation
title_fullStr	Profiling of three H3F3A-mutated and denosumab-treated giant cell tumors of bone points to diverging pathways during progression and malignant transformation
title_full_unstemmed	Profiling of three H3F3A-mutated and denosumab-treated giant cell tumors of bone points to diverging pathways during progression and malignant transformation
title_sort	profiling of three h3f3a-mutated and denosumab-treated giant cell tumors of bone points to diverging pathways during progression and malignant transformation
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/7e362e1fc5aa4bdcbb09fa7a3c4adf92
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Profiling of three H3F3A-mutated and denosumab-treated giant cell tumors of bone points to diverging pathways during progression and malignant transformation

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