Clinical radiosensitivity: role of DNA repair

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This proposal will focus on determining the effect that disruption of molecules involved in repairing DNA has on development of adverse reactions following cancer radiation treatment. Radiation is efective for cancer but tissues that reside next to the tumour are also exposed to radiation (which can damage DNA) during radiotherapy. About 1-5% of radiotherapy patients develop unexpectedly severe side effects in their normal tissues. The dose of radiation used for treatment to the rest of patients (>95%) is restrained to assure only a small proportion risk developing severe reactions. If one could predict which individuals were more susceptible to these reactions, then their large dose could be lowered to avoid the problem, and importantly, the dose could be increased for the majority of the patients, which would lead to a higher cancer cure rate. There are over 130 genes involved in repairing DNA. We hypothesize that dysfunctional DNA repair molecules are likely candidates to cause radiosensitivity in these individuals. In fact, a few of these genes have already been found to cause radiosensitivity, but we aim to assess all of the DNA repair genes in samples from patients that have had severe reactions to radiotherapy. Here we will use biospecimens, unique to our study and obtained from clinically radiosensitive cancer patients. We will use very sensitive, state-of-the-art procedures to test RNA and protein levels in our patients' cells and the latest technology to test what happens when candidate DNA repair molecule levels are altered. Additionally, we will determine the changes in DNA repair molecule numbers in response to different doses of radiation. We anticipate that results from these experiments will lead to the development of a clinical assay to test the likelihood of an individual having a severe reaction to radiotherapy, thus allowing individualization of treatment and, reducing radiotherapy side effects ultimately increasing cancer cure rates.