Reduced oxidative stress response as a risk factor for normal tissue damage after radiotherapy: a study on mandibular osteoradionecrosis
(English)Manuscript (preprint) (Other academic)
The use of radiotherapy (RT) to treat cancer involves exposure of normal tissues. Factors that promote the development of normal tissue damage are poorly understood. An increased individual sensitivity to ionizing radiation is a likely candidate, but general phenotypes for late adverse effects of RT are difficult to define. We have found osteoradionecrosis (ORN) in the mandible as a well-defined model phenotype for an in-depth study of clinical and biological risk factors for developing late adverse effects to RT.
A cohort of patients with stage 2/3 ORN following RT for head and neck cancer (HCN) was studied and compared to a closely matched control group. Blood samples from the patients were collected and irradiated in vitro and the capacity to handle radiation-induced oxidative stress was investigated by measuring the level of 8-oxo-dG in serum 60 min post exposure. The patients were also genotyped for eight SNPs in genes involved in the oxidative stress response and previously studied in the context of individual radiosensitivity. Results from these endpoints were analyzed in conjunction with clinical data using multivariate analysis and an ORN risk model was constructed.
A significant difference in 8-oxo-dG levels was found between the patient cohorts, indicating a heterogeneous response to oxidative stress induced by the in vitro γ-radiation. The SNP rs1695 in GSTP1 was found to be significantly more frequent in the ORN+ compared to ORN- group. Multivariate analysis of the clinical and biological factors revealed concomitant brachytherapy plus the two biomarkers to be the most significant.
Interpretation: The current study indicates that patient-related factors are a major source of individual variation in normal tissue response to RT. Two of the studied genetic biomarkers are strong factors in the described risk model of ORN.
Radiotherapy, normal tissue effects, head and neck cancer, osteoradionecrosis, 8-oxo-dG, SNP, oxidative stress, multivariate analysis, modelling
Strålterapi, normalvävnadseffekter, huvud/halscancer, osteoradionekros, 8-oxo-dG, SNP, oxidativ stress, multivariat analys, modellering
Biochemistry and Molecular Biology
Research subject Molecular Biosciences
IdentifiersURN: urn:nbn:se:su:diva-96442OAI: oai:DiVA.org:su-96442DiVA: diva2:665921
FunderSwedish Radiation Safety Authority