A comprehensive genomic analysis of 293 adult lower-grade gliomas identified three molecular subtypes that were more accurately defined by IDH, 1p/19q, and TP53 status than by histologic class. Gliomas with IDH mutations and 1p/19q codeletion had the most favorable clinical outcomes, while those with IDH mutations but no 1p/19q codeletion had TP53 mutations. Gliomas without IDH mutations showed clinical and genomic similarities to glioblastomas. The study integrated data from multiple platforms, including exome sequencing, DNA copy number, DNA methylation, mRNA expression, microRNA expression, and protein expression, to identify molecular subtypes and their clinical significance. The results suggest that molecular classification is more reliable than histologic classification for predicting clinical outcomes. The study also identified significant mutations and copy-number alterations in different subtypes, highlighting the importance of molecular markers in glioma diagnosis and treatment. The findings support the use of IDH and 1p/19q status as key markers for classifying lower-grade gliomas and improving clinical decision-making. The study was funded by the National Institutes of Health.A comprehensive genomic analysis of 293 adult lower-grade gliomas identified three molecular subtypes that were more accurately defined by IDH, 1p/19q, and TP53 status than by histologic class. Gliomas with IDH mutations and 1p/19q codeletion had the most favorable clinical outcomes, while those with IDH mutations but no 1p/19q codeletion had TP53 mutations. Gliomas without IDH mutations showed clinical and genomic similarities to glioblastomas. The study integrated data from multiple platforms, including exome sequencing, DNA copy number, DNA methylation, mRNA expression, microRNA expression, and protein expression, to identify molecular subtypes and their clinical significance. The results suggest that molecular classification is more reliable than histologic classification for predicting clinical outcomes. The study also identified significant mutations and copy-number alterations in different subtypes, highlighting the importance of molecular markers in glioma diagnosis and treatment. The findings support the use of IDH and 1p/19q status as key markers for classifying lower-grade gliomas and improving clinical decision-making. The study was funded by the National Institutes of Health.