Genetic divergence and therapy-driven evolution between initial and recurrent glioma

Low-grade gliomas are slow-growing tumors that often undergo malignant progression to an aggressive high-grade glioblastoma (GBM) with a significantly worse prognosis. Treatment options after surgical resection include temozolomide (TMZ), an alkylating chemotherapeutic which is cytotoxic but can induce C>T/G>A transition mutations when DNA mismatch repair is deficient. However, the extent and clinical impact of TMZ-associated mutagenesis is poorly understood. To investigate the genomic evolution of recurrent tumors and the contribution of TMZ-induced mutagenesis to their mutational landscape, we sequenced the exomes of 23 initial low-grade gliomas and their patient-matched recurrences resected up to 11 years later. We identified a diverse set of evolutionary trajectories that included unexpected losses of canonical driver mutations and radical differences in the genetic relatedness of initial-recurrent tumor pairs. Notably, we found that the recurrent tumors of six patients treated after surgery with TMZ became hypermutated and subsequently recurred as GBM. In each, TMZ-associated mutations altered the function of key cancer genes in pathways involved in malignant progression, including activating mutations in MTOR and PIK3CA, and inactivating mutations in CDKN2A, PTEN, and RB1. These findings suggest that this widely used chemotherapeutic agent has the potential to accelerate tumor evolution with unintended clinical and biological consequences. The ongoing evolution of the genetic landscape in all recurrences emphasizes the need for a longitudinal approach to personalized cancer genomics