First radiobiological characterization of the McCune-Albright syndrome: influence of the ATM protein and effect of statins plus bisphosphonates treatment

Purpose MacCune-Albright syndrome (MAS) is a rare autosomal dominant osteo-hormonal disorder. MAS is characterized by a severe form of polyostotic fibrous dysplasia, 'cafe-au-lait' pigmentation of the skin and multiple endocrinopathies. MAS was shown to be caused by mosaic missense somatic mutations in the GNAS gene coding for the alpha-subunit of the stimulatory G-protein. MAS is also associated with radiation-induced malignant tumors, like osteosarcoma, fibrosarcoma and chondrosarcoma but their origin remains misunderstood. In parallel, bisphosphonates treatment was shown to improve the MAS patients' outcome, notably by increasing bone density but, again, the molecular mechanisms supporting these observations remain misunderstood. Materials and methods Here, by using fibroblast and osteoblast cell lines derived from 2 MAS patients, the major radiobiological features of MAS were investigated. Notably, the clonogenic cell survival, the micronuclei and the gamma H2AX, pATM and MRE11 immunofluorescence assays were applied to MAS cells. Results It appears that cells from the 2 MAS patients are associated with a moderate but significant radiosensitivity, a delayed radiation-induced nucleoshuttling of the ATM kinase likely caused by its sequestration in cytoplasm, suggesting impaired DNA double-strand breaks (DSB) repair and signaling in both fibroblasts and osteoblasts. Such delay may be partially corrected by using bisphosphonates combined with statins, which renders cells more radioresistant. Conclusions Our findings represent the first radiobiological characterization of fibroblasts and osteoblasts providing from MAS patients. Although the number of studied cases is reduced, our findings suggest that the MAS cells tested belong to the group of syndromes associated with moderate but significant radiosensitivity. Further investigations are however required to secure the clinical transfer of the combination of bisphosphonates and statins, to reduce the disease progression and to better evaluate the potential risks linked to radiation exposure.

Automated summary

MacCune-Albright syndrome (MAS) is a rare autosomal dominant osteo-hormonal disorder characterized by severe polyostotic fibrous dysplasia, 'cafe-au-lait' pigmentation, and multiple endocrinopathies. MAS is caused by somatic mutations in the GNAS gene and is associated with radiation-induced malignant tumors. Bisphosphonates treatment has been shown to improve outcomes for MAS patients by increasing bone density. The study found that MAS cells exhibit moderate but significant radiosensitivity, potentially due to impaired DNA repair and signaling pathways. Further research is needed to explore the clinical application of bisphosphonates and statins in MAS treatment, and to assess potential risks associated with radiation exposure.