From bone alterations to tumours: Genetic drivers linking Paget's disease of bone to cancer.

Paget's disease of bone (PDB) is a metabolic disorder characterized by abnormal bone remodelling and a strong genetic component. Several genes are involved, with distinct genetic backgrounds correlating with specific clinical manifestations. Mutations in SQSTM1 are most commonly associated with classical PDB, while alterations in ZNF687 and PFN1 define rarer, more aggressive variants that may progress to bone tumours such as giant cell tumour and osteosarcoma. Furthermore, mutations in VCP and TNFRSF11A are linked to syndromic forms where PDB coexists with other clinical features. This review examines the physiological roles of these genes and the pathogenic effects of their mutations in PDB. Notably, many of the genes implicated are also established oncogenes or tumour suppressors, suggesting a functional overlap between PDB and cancer biology. These genes are implicated in malignancies including hepatocellular carcinoma, lung adenocarcinoma, and breast cancer. A central shared mechanism is the dysregulation of the NFκB pathway, which in PDB leads to increased osteoclast differentiation, and in cancer fosters a pro-inflammatory environment that promotes tumorigenesis. Understanding how altered bone remodelling intersects with cancer‑related signalling highlights shared molecular vulnerabilities that could be exploited therapeutically, and provides a framework for future mechanistic and translational studies in PDB‑associated cancer.