Abstract 2974: Comprehensive and integrative genomic characterization of diffuse lower grade gliomas

Abstract

Abstract Background: Diffuse low and intermediate grade gliomas (LGG; WHO grades II and III) have highly variable clinical behaviors that are not optimally predicted by histology; some are indolent, while others quickly progress to glioblastoma. Uncertainty is compounded by inter-observer variability in diagnosis, in part due to modest correlation between histology and biologic classes. Mutations in isocitrate dehydrogenase (IDH), TP53, ATRX, and co-deletion of chromosomes 1p and 19q are implicated as clinically relevant LGG markers. Methods: We performed a comprehensive genome-wide analysis of 293 LGG, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA and microRNA expression and targeted protein expression. Molecular data was integrated with clinical outcomes to identify biologically robust LGG subtypes. Results: We uncovered 19 mutated genes, including recognized drivers and novel mutations. Unsupervised clustering of genome-wide data from RNA-, DNA- and DNA methylation platforms uncovered concordant classification of three robust, non-overlapping LGG subtypes that were captured with highest correlation by IDH and 1p/19q status. The large majority of IDH wild-type LGG showed strikingly similar genomic aberrations and clinical behavior to primary glioblastoma. Nearly all IDH-mutant LGG lacking 1p/19q co-deletion had mutations in TP53 (94%) and ATRX inactivation (86%). IDH-mutant, 1p/19q-co-deleted LGG had most favorable clinical outcomes and harbored mutations in CIC, FUBP1, NOTCH1 and the TERT promoter. Conclusions: Integration of genome-wide data from multiple platforms cleanly delineates three LGG molecular subtypes concordant with IDH and 1p/19q status: IDH-mutant LGG are either 1p/19 co-deleted or TP53 mutant, whereas most IDH wild-type LGG are molecularly and clinically similar to glioblastoma. Overall, results support a molecular-based, clinically relevant classification for implementation into routine clinical practice. Citation Format: Daniel J. Brat, The Cancer Genome Atlas (TCGA) Research Network. Comprehensive and integrative genomic characterization of diffuse lower grade gliomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2974. doi:10.1158/1538-7445.AM2015-2974