Longitudinal multi-omics characterization of the malignant evolution in multirelapsing glioblastoma

Linking glioblastoma (GBM) evolution to clinical progression is challenged by multiple factors, including tumor location for repeated sample collection, and short patient survival. In a single individual, we collected and analysed samples from 11 operations distributed across 31 months of multi-relapsing and multifocal GBM, including terminal leptomeningeal progression. All samples shared genomic ancestry of the retinoblastoma protein 1 (RB1) and neurofibromin 1 (NF1) mutations while advanced progression and extracranial metastases featured mutations of tuberous sclerosis complex 2 (TSC2), PBRM1, CD22 and Fanconi anemia supplementation group I (FANCI), correlated with clinical resistance to immunotherapies and DNA-damaging agents. Single-cell analytics revealed distinct yet reversible shifts in response to the precision medicine arsenal. GBM parenchymal dissemination and extracranial progression were associated with strengthening of neuron-like cell phenotypes. Our multidimensional study describes GBM evolution over a rarely reported time scale, and provides a valuable resource linking genetic, molecular, cellular and clinical progressions.