Adult gliomas represent a diverse group of tumors characterized by differing genetic signatures and clinical presentations. Using unsupervised latent class analysis (LCA) of glioma somatic variants (independent of diagnosis), we identified biologically and clinically relevant subclasses associated with distinct clinical outcomes while highlighting the landscape of glioma driver events.
LCA was performed on somatic variants from 765 adult glioma patients (grade II-IV, TCGA dataset) using expectation-maximization and Newton-Raphson algorithms to determine maximum likelihood estimates of model parameters. Survival outcomes per class were generated using Kaplan–Meier and COX proportional hazard analysis.
LCA revealed seven distinct classes of gliomas. Classes 1 and 2 were defined by IDH1/2 mutations. Class 1 showed co-occurring CIC mutations and 1p/19q co-deletion (oligodendroglial lineage) whereas Class 2 enriched for co-occurring TP53 and ATRX mutations (astrocytic lineage). Class 3 was characterized by dysregulated cell cycle signaling largely due to alterations in MDM2/CDK4 whereas Class 4 enriched for activation of PI3K signaling mediated through alterations in NF1, PIK3CA, and PTEN. Receptor tyrosine kinase activation including EGFR and PDGFRA/KDR/KIT defined Class 5 and 7, respectively. Class 6 enriched for gliomas with gains of chr 7 but without PTEN alterations. Median survival was greatest for classes defined by IDH1/2 (2907 days Class 1, 2000 days Class 2) and poorest for Class 4 (383 days).
LCA of glioma somatic variants reveal biologically and clinically relevant classes independent of diagnosis that are associated with significant differences in patient survival. The genomic classes seem to involve different underlying molecular mechanisms that can become altered in gliomas. These findings suggest that LCA-based glioma classification may serve as a primary predictor for clinical outcomes and provide objective data to be used in clinical management and trial design.
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All authors have declared no conflicts of interest.