Severe PATCHED1 Deficiency in Cancer-Prone Gorlin Patient Cells Results in Intrinsic Radiosensitivity

Area of Science:

• Genetics
• Oncology
• Radiation Biology

Background:

• Gorlin syndrome (basal-cell nevus syndrome) is a genetic disorder associated with increased cancer risk.
• The role of PTCH1 gene mutations in Gorlin syndrome and its impact on cellular radiosensitivity remain debated.
• Understanding radiosensitivity in Gorlin syndrome is crucial for managing cancer treatment and predicting patient outcomes.

Purpose of the Study:

• To investigate the correlation between PTCH1 gene expression and intrinsic radiosensitivity in fibroblasts from Gorlin syndrome patients.
• To determine if PTCH1 deficiency influences cellular responses to both high and low doses of ionizing radiation.

Main Methods:

• Fibroblast cell cultures from Gorlin syndrome patients and healthy donors were used.
• Cellular radiosensitivity was assessed using cell-survival assays after gamma-ray irradiation.
• Gene expression of PTCH1 and DNA damage response genes was analyzed using RT-PCR and Western blotting.
• DNA damage and repair mechanisms were evaluated using foci assays, and PTCH1 knockdown was performed in normal cells.

Main Results:

• Cells from Gorlin syndrome patients with severe PATCHED1 protein deficiency exhibited significantly increased radiosensitivity to both high and low radiation doses.
• Heterozygous mutations in the PTCH1 gene were identified in some radiosensitive cell strains, explaining the protein deficiency.
• DNA damage response pathways were deregulated in radiosensitive cells, while double-strand break repair recognition remained unaffected.
• PTCH1 knockdown in normal cells resulted in reduced survival after irradiation, confirming the gene's role in radiosensitivity.

Conclusions:

• There is an inverse correlation between PTCH1 expression levels and cellular radiosensitivity in Gorlin syndrome.
• This finding provides a potential explanation for conflicting previous reports on radiosensitivity in Gorlin syndrome.
• The study suggests a basis for prognostic screening of radiosensitive Gorlin syndrome patients with PTCH1 mutations.