Research Papers:

The distinct clinical features of giant cell tumor of bone in pagetic and non-pagetic patients are associated with genetic, biochemical and histological differences

Giuseppina Divisato, Federica Scotto di Carlo, Laura Pazzaglia, Riccardo Rizzo, Domenico A. Coviello, Maria Serena Benassi, Piero Picci, Teresa Esposito and Fernando Gianfrancesco _

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Oncotarget. 2017; 8:63121-63131. https://doi.org/10.18632/oncotarget.18670

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Giuseppina Divisato1, Federica Scotto di Carlo1,2, Laura Pazzaglia3, Riccardo Rizzo4, Domenico A. Coviello5, Maria Serena Benassi3, Piero Picci3, Teresa Esposito1,6 and Fernando Gianfrancesco1

1Institute of Genetics and Biophysics Adriano Buzzati-Traverso, National Research Council of Italy, Naples, Italy

2Department of Environmental, Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), University of Campania Luigi Vanvitelli, Caserta, Italy

3Laboratory of Experimental Oncology, Rizzoli Orthopaedic Institute, Bologna, Italy

4Institute of Protein Biochemistry, National Research Council of Italy, Naples, Italy

5Laboratory of Human Genetics, Galliera Hospital, Genova, Italy

6IRCCS INM Neuromed, Pozzilli, Italy

Correspondence to:

Fernando Gianfrancesco, email: [email protected]

Keywords: bone cancer, GCT, pagetic GCT, ZNF687, H3F3A

Received: August 04, 2016    Accepted: May 23, 2017    Published: June 27, 2017


Giant Cell Tumor of Bone (GCT) is a tumor characterized by neoplastic mesenchymal stromal cells and a high number of osteoclast-like multinucleated giant cells. Rarely, GCT could arise in bones affected by Paget’s disease of bone (GCT/PDB). Although it is already known that GCT/PDB and GCT show a different clinical profile regarding the age-onset and skeletal localization, our deep clinical comparison between the two GCT/PDB and GCT cohorts, permitted us to identify additional differences (e.g. focality, ALP serum levels, the 5-year survival rate and the familial recurrence), strongly suggesting a different molecular basis. Accordingly, driver somatic mutations in H3F3A and IDH2 were described in GCT patients, while we recently identified a germline mutation in ZNF687 as the genetic defect of GCT/PDB patients.

Here, we detected H3F3A mutations in our GCT cohort, confirming its molecular screening as the elected diagnostic tool, and then we excluded the two-hit in H3F3A and IDH2 as the trigger event for the GCT/PDB development. Importantly, we also identified an alternative biochemical profile with GCT/PDB not exhibiting the up-regulation of the GCT marker FGFR2IIIc. Finally, our histological analysis also showed a different appearance of the two forms of the tumor, with GCT/PDB showing a higher number of osteoclast-like giant cells (twice), with an abnormal number of nuclei per cell, corroborating its different behaviour in terms of neoplastic properties.

We demonstrated that the distinct clinical features of pagetic and conventional GCT are associated with different genetic background, resulting in a specific biochemical and histological behaviour of the tumour.

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