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

Abstract

Purpose

MacCune–Albright syndrome (MAS) is a rare autosomal dominant osteo-hormonal disorder. MAS is characterized by a severe form of polyostotic fibrous dysplasia, ‘café-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 γH2AX, 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.

Keywords:

• MacCune–Albright syndrome
• radiation
• radiosensitivity
• ATM
• DNA double-strand breaks

Acknowledgments

JTB was awarded by the Association des Gueules Cassées.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Commissariat Général à l'Investissement (CGI) (INDIRA project), the Institut National du Cancer (INCA) (PROUST Project), the Centre National d’Etudes Spatiales (CNES) (BERNADOTTE Project).

Notes on contributors

Jean-Thomas Bachelet

Dr. Jean-Thomas Bachelet is a maxillo-facial surgeon and PhD student in the UA8 Inserm and focuses on the radiosensitivity syndromes.

Adeline Granzotto

Adeline Granzotto is an Engineer-assistant in the UA8 Inserm Unit and focuses on the cancer proneness syndromes.

Mélanie Ferlazzo

Mélanie Ferlazzo is post-doctorant fellow in the UA8 Inserm Unit and focuses on the radiosensitivity syndromes.

Laurène Sonzogni

Laurène Sonzogni is an Engineer-assistant in the UA8 Inserm Unit and is responsible of the collection of the fibroblast cell lines.

Elise Berthel

Elise Berthel is post-doctorant fellow in the UA8 Inserm Unit and focuses on the aging syndromes.

Clément Devic

Clément Devic is a PhD student in the UA8 Inserm Unit and focuses on the low-dose phenomena.

Nicolas Foray

Nicolas Foray is Director of Research in INSERM, Director of the UA8 Unit and expert in radiobiology.