The present invention relates to a new diagnostic marker for Paget’s disease of bone (PDB) and bone tumors associated therewith, such as Giant Cell Tumor (GCT). This marker is represented by the ZNF687 gene that, when mutated, is responsible for an aggressive form of PDB. If not treated, these PDB patients usually undergo the neoplastic degeneration.

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Paget disease of bone (PDB) is the second most common bone remodeling disease after osteoporosis. It is a chronic and disabling disease, affecting up to 1% of middle-aged patients (~50 years old). PDB prevalence notably differs amongst different Countries. This disease is most common (5,4%) in the United Kingdom, less in Japan (0,00028%).


Paget's disease of bone is a metabolic disorder that affects the skeletal system and is due to a dysregulation between the two types of cells that contribute to bone metabolism: osteoclasts (responsible for bone resorption) and osteoblasts (responsible for bone formation). This unbalance results in pain, deformity and fractures. However, the most fearful complication is represented by the tumor degeneration of the affected bones into osteosarcoma or, more rarely, giant cell tumor. A pharmacological treatment is available, using next generation bisphosphonates, which are able to block the evolution of the disease, especially if detected early. It is therefore absolutely important to diagnose the disease on time.
Recently, we found that patients with the very aggressive form of the disease that degenerates into giant cell tumor are mutated in the ZNF687 gene. The development of a diagnostic kit would make it possible to identify patients carrying the mutation early and subject them to prompt drug treatment, thus avoiding the onset of giant cell tumor.

Current Technology Limitations

Paget's disease is often asymptomatic in early stages and symptoms generally arise in the late stage: the most common symptom is bone pain, which can occur in one or more skeletal areas. Bone deformities and fractures typically arise in the advanced stage of the disease. For diagnostic confirmation, instrumental investigations such as radiography, bone scintigraphy and the dosage of some markers of bone metabolism are necessary (the most common is total alkaline phosphatase), generally increased in case of disease.
All these clinical and instrumental analyses can be anticipated by the molecular analysis that identifies carriers of the mutation in their early stage when a pharmacological treatment can block and/or control its pathological course.
The ZNF687 gene, responsible for a severe form of Paget’s disease of bone complicated by giant cell tumor degeneration, has been identified in the Molecular Genetics and Genomics laboratory at CNR of Naples in 2016. Previously, there was no diagnostic markers for this disorder.

Killer Application

The diagnostic procedure is based on the combination of different molecular assays: DNA extraction, amplification of the gene of interest by polymerase chain reaction (PCR), nucleotide sequencing by Sanger method.
This workflow would lead to the development of a molecular tool that, with few steps and few reagents, may be able to make an accurate molecular diagnosis of the disease.

Our Technology and solutions

We propose the development of a diagnostic kit able to detect the presence of mutations in the ZNF687 gene in patients affected by Paget's disease of the bone.
Through a blood sample, it will be possible to extract the DNA from the patient, subject to molecular analyses and finally sequence the causative gene.

The genetic test consists in the sequencing of the entire ZNF687, with particular attention to the exon 6 of the same gene, where the P937R mutation that causes giant cell tumor degeneration may be present.


The main advantage is the possibility of identifying patients with Paget's disease of bone with a mutation in the ZNF687 gene and therefore predisposed to the development of giant cell tumor. A prompt and adequate pharmacological treatment of these patients could avoid the onset of giant cell tumor.

Two categories of patients could benefit from the existence of a diagnostic kit:
1. relatives of patients affected by Paget's disease of bone and mutated in the ZNF687 gene to verify their potential carrier status which can therefore be monitored along the time.
2. pagetic patients with a clinical diagnosis who may be predisposed to tumor development.


Interaction with pharmaceutical companies interested and/or involved in bone metabolism disorders and/or in neoplastic disorders for the development of the diagnostic kit.

An idea for the development of the diagnostic kit could include several steps:
a tube could contain all the enzymes for DNA extraction.
a second tube could contain enzymes to allow gene PCR amplification.
a third tube containing enzymes for DNA sequencing.

Development stage

The European patent n. 15732388 was deposited in Italy, France, Germany, United Kingdom and Belgium. It represents the starting point for an interaction with pharmaceutical companies interested in bone metabolism disorders and/or neoplastic disorders for the development of a diagnostic kit for the identification of mutations in the ZNF687 gene. This could be used by public or private hospitals and/or genetic diagnosis Centers.

There are currently no ongoing negotiations with companies for the development of an experimental proof of concept for the early diagnosis of this form of Paget's disease associated with neoplastic transformation in giant cell tumor.

The Technology Readiness Level can be considered at a level of TRL 2 (formulation of a technological concept).

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