2. Academic Validation
  3. ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor

ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor

  • Am J Hum Genet. 2016 Feb 4;98(2):275-86. doi: 10.1016/j.ajhg.2015.12.016.
Giuseppina Divisato 1,  Daniela Formicola 1,  Teresa Esposito 1,  Daniela Merlotti 2,  Laura Pazzaglia 3,  Andrea Del Fattore 4,  Ethel Siris 5,  Philippe Orcel 6,  Jacques P Brown 7,  Ranuccio Nuti 2,  Pasquale Strazzullo 8,  Maria Serena Benassi 3,  M Leonor Cancela 9,  Laetitia Michou 7,  Domenico Rendina 8,  Luigi Gennari 2,  Fernando Gianfrancesco 10
Affiliations

Affiliations

  • 1 Institute of Genetics and Biophysics "Adriano Buzzati-Traverso," National Research Council of Italy, 80131 Naples, Italy.
  • 2 Department of Medicine, Surgery and Neurosciences, University of Siena, Siena 53100, Italy.
  • 3 Laboratory of Experimental Oncology, Rizzoli Orthopaedic Institute, Bologna 40136, Italy.
  • 4 Bambino Gesù Children's Hospital, Regenerative Medicine Unit, Rome 00146, Italy.
  • 5 Department of Medicine, Columbia University Medical Centre, New York, NY 10032, USA.
  • 6 Pôle Appareil Locomoteur, Service de Rhumatologie B, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris 75010, France.
  • 7 Division of Rheumatology, Department of Medicine, Université Laval, Québec, QC 42178, Canada.
  • 8 Department of Medicine and Surgery, Federico II University, Naples 80131, Italy.
  • 9 Department of Biomedical Sciences and Medicine and Centre of Marine Sciences, University of Algarve, Faro 8005-139, Portugal.
  • 10 Institute of Genetics and Biophysics "Adriano Buzzati-Traverso," National Research Council of Italy, 80131 Naples, Italy. Electronic address: fernando.gianfrancesco@igb.cnr.it.
PMID: 26849110 DOI: 10.1016/j.ajhg.2015.12.016
Abstract

Paget disease of bone (PDB) is a skeletal disorder characterized by focal abnormalities of bone remodeling, which result in enlarged and deformed bones in one or more regions of the skeleton. In some cases, the pagetic tissue undergoes neoplastic transformation, resulting in osteosarcoma and, less frequently, in giant cell tumor of bone (GCT). We performed whole-exome Sequencing in a large family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites, and we identified the c.2810C>G (p.Pro937Arg) missense mutation in the zinc finger protein 687 gene (ZNF687). The mutation precisely co-segregated with the clinical phenotype in all affected family members. The Sequencing of seven unrelated individuals with GCT associated with PDB (GCT/PDB) identified the same mutation in all individuals, unravelling a founder effect. ZNF687 is highly expressed during osteoclastogenesis and osteoblastogenesis and is dramatically upregulated in the tumor tissue of individuals with GCT/PDB. Interestingly, our preliminary findings showed that ZNF687, indicated as a target gene of the NFkB transcription factor by ChIP-seq analysis, is also upregulated in the peripheral blood of PDB-affected individuals with (n = 5) or without (n = 6) mutations in SQSTM1, encouraging additional studies to investigate its potential role as a biomarker of PDB risk.

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