Genetic of radiation-induced toxicities in cancer patients

Cancer remains a leading cause of death globally, and radiotherapy has contributed significantly to improvements in the treatment of cancer patients. However, not every cancer responds to radiotherapy in the same way. Despite applying uniform treatment protocols for radiotherapy to minimize damage to the surrounding healthy tissue, a large patient-to-patient variability exists in radiation-induced toxicities. Many cancer patients achieve survivorship at the cost of treatment complications occurring in normal tissues. However, the solution is not to eliminate radiation exposure but to protect individuals who are the most sensitive to radiation and minimize dose and exposure to all individuals.In this thesis, I focused on uncovering the underlying genetic causes of individual variation in sensitivity to radiation in cancer patients. I applied various genetic epidemiological designs, methods, and concepts in a range of studies to identify genetic variants associated with radiation-induced toxicities in cancer patients. Eventually, this thesis identified several genomic regions associated with radiation-induced toxicities. In addition, the thesis showed for the first time, radiation-induced toxicities are mostly heritable and predictable by genetic profiles of cancer patients. The identified predictors aim to contribute to an algorithm to improve the guidelines of therapeutic decisions. Patients at high risk of developing radiation-induced toxicities may be offered an alternative treatment approach, or, for patients who have received radiotherapy, advanced planning corrections can be introduced to better-individualized radiotherapy treatment. In addition to predictive and prognostic testing, the products of the identified genes could become targets for innovative therapies in susceptible individuals