Abstract BACKGROUND CNS WHO grade 1 pediatric low-grade gliomas (pLGGs) have an overall excellent survival. A small but relevant proportion of these patients, however, suffer from severe disease burden reflected in recurrent progression, metastasis or even death. To unravel clinicomolecular tumor characteristics that identify these ‘pLGG-higher risk’ patients we retrospectively analyzed clinical and molecular data of 223 patients from our center. METHODS All tumors were classified using histology, DNA methylation profiling and whole transcriptome analysis (RNA sequencing), with whole exome or panel DNA sequencing in a subset of cases, revealing a driver alteration in 100% of cases. Progression of disease was defined as continuous tumor growth upon treatment or need for multiple treatments. The effect of clinical and molecular variables on progression free survival was analyzed with the univariate and multivariate cox proportional hazard model. RESULTS The median follow-up of the entire cohort was 3,4 years. In univariate analyses the risk of progression significantly decreased with age (in years) at diagnosis (HR 0.92,p<0.001). For tumor location using hemispheric tumors as reference, chiasm/suprasellar LGGs showed a significantly higher risk of progression (HR 2.96,p<0.001). Type of molecular driver and sex was not associated with progression. In a multivariable model including age, location and driver, there was no longer a significant effect on progression for age but the effect of chiasm/suprasellar location remained intact. Furthermore, NF1 (HR 0.37,p0.02), and posterior fossa LGG (HR 0.24,p0.03) were both significantly associated with a lower risk of progression. CONCLUSIONS Our multivariate results show that the ‘pLGG-higher risk’ patients were characterized by a tumor in the chiasm/suprasellar location, while molecular driver (at least so far) did not affect risk of progression. Future work will focus on extending the cohort and integrating other multiomic data enabling to compose a prediction model for higher risk pLGG.