Cancer is a leading cause of death globally, and the incidence is expected to increase to 28.4 million cases by 2040. Precision oncology seeks to address this challenge through the identification and application of biomarkers to personalize treatment in a genomics-based, biomarker-driven approach. In this thesis, I aimed to comprehensively analyze the genomic impact of cancer chemotherapy and radiotherapy, both of which are genotoxic and expected to leave a mutational footprint in the cancer genome. By integration with comprehensive clinical data, I assessed the prognostic and predictive value of the signatures identified. My thesis has a strong focus on diffuse gliomas, the most common and aggressive type of brain tumors in adults, which have a poor prognosis despite intensive multimodal treatment. Standard therapy for diffuse gliomas includes surgery, radiotherapy, and chemotherapy. I started by examining the genomic impact of the alkylating agent temozolomide in gliomas, and subsequently analyzed the genomic effects of radiotherapy in a pan- cancer setting. Following the genomic analyses, I investigated the longitudinal non- genetic changes in gliomas associated with TMZ-associated hypermutation and RT- associated deletion signatures. To potentially overcome translational barriers in cancer, I propose the use of spontaneous canine gliomas as a potential model for preclinical and translational science to facilitate the knowledge transfer into clinical practice. I conclude by discussing these findings, focusing on the potential to integrate them into a precision oncology framework and identify novel therapeutic avenues. The use of next-generation sequencing technology and comprehensive molecular characterization have facilitated diagnostic advances in the field of gliomas, including the use of molecular markers and the updated WHO Classification of Tumors of the Central Nervous System. These advances have yet to be translated into successful treatment strategies. My analyses provide valuable insights into the mechanisms of treatment resistance and open future opportunities for biomarker-guided treatment strategies as part of a precision oncology approach.