title: ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor.
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.
authors: Institute of Genetics and Biophysics "Adriano Buzzati-Traverso," National Research Council of Italy, 80131 Naples, Italy.
authors: Giuseppina
authors: G
authors: Divisato
authors: Institute of Genetics and Biophysics "Adriano Buzzati-Traverso," National Research Council of Italy, 80131 Naples, Italy.
authors: Daniela
authors: D
authors: Formicola
authors: Institute of Genetics and Biophysics "Adriano Buzzati-Traverso," National Research Council of Italy, 80131 Naples, Italy.
authors: Teresa
authors: T
authors: Esposito
authors: Department of Medicine, Surgery and Neurosciences, University of Siena, Siena 53100, Italy.
authors: Daniela
authors: D
authors: Merlotti
authors: Laboratory of Experimental Oncology, Rizzoli Orthopaedic Institute, Bologna 40136, Italy.
authors: Laura
authors: L
authors: Pazzaglia
authors: Bambino Gesù Children's Hospital, Regenerative Medicine Unit, Rome 00146, Italy.
authors: Andrea
authors: A
authors: Del Fattore
authors: Department of Medicine, Columbia University Medical Centre, New York, NY 10032, USA.
authors: Ethel
authors: E
authors: Siris
authors: Pôle Appareil Locomoteur, Service de Rhumatologie B, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris 75010, France.
authors: Philippe
authors: P
authors: Orcel
authors: Division of Rheumatology, Department of Medicine, Université Laval, Québec, QC 42178, Canada.
authors: Jacques P
authors: JP
authors: Brown
authors: Department of Medicine, Surgery and Neurosciences, University of Siena, Siena 53100, Italy.
authors: Ranuccio
authors: R
authors: Nuti
authors: Department of Medicine and Surgery, Federico II University, Naples 80131, Italy.
authors: Pasquale
authors: P
authors: Strazzullo
authors: Laboratory of Experimental Oncology, Rizzoli Orthopaedic Institute, Bologna 40136, Italy.
authors: Maria Serena
authors: MS
authors: Benassi
authors: Department of Biomedical Sciences and Medicine and Centre of Marine Sciences, University of Algarve, Faro 8005-139, Portugal.
authors: M Leonor
authors: ML
authors: Cancela
authors: Division of Rheumatology, Department of Medicine, Université Laval, Québec, QC 42178, Canada.
authors: Laetitia
authors: L
authors: Michou
authors: Department of Medicine and Surgery, Federico II University, Naples 80131, Italy.
authors: Domenico
authors: D
authors: Rendina
authors: Department of Medicine, Surgery and Neurosciences, University of Siena, Siena 53100, Italy.
authors: Luigi
authors: L
authors: Gennari
authors: Institute of Genetics and Biophysics "Adriano Buzzati-Traverso," National Research Council of Italy, 80131 Naples, Italy. Electronic address: fernando.gianfrancesco@igb.cnr.it.
authors: Fernando
authors: F
authors: Gianfrancesco
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D005091:Exons; D005260:Female; D018703:Founder Effect; D015972:Gene Expression Regulation, Neoplastic; D005870:Giant Cell Tumors / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010001:Osteitis Deformans / Q000235:genetics*; D010010:Osteoclasts / Q000378:metabolism; D010375:Pedigree; D015854:Up-Regulation; D015027:Zebrafish / Q000235:genetics; D016335:Zinc Fingers / Q000235:genetics*