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Unsupervised latent class analysis of adult glioma variant profiles reveals biologically and clinically relevant subclasses

Date

10 Oct 2016

Session

Poster display

Presenters

Manna Chang

Citation

Annals of Oncology (2016) 27 (6): 545-551. 10.1093/annonc/mdw393

Authors

M. Chang1, S. Ramkissoon2, H. Bokhari3, A. Fichtenholtz1, S. Ali4, J.S. Ross2, E. Neumann1

Author affiliations

  • 1 Knowledge Informatics, Foundation Medicine, 02141 - Cambridge/US
  • 2 Pathology, Foundation Medicine, Inc., 02141 - Cambridge/US
  • 3 Computational Biology, Cornell University, 14850 - Ithaca/US
  • 4 Clinical Development, Foundation Medicine, Inc., 02141 - Cambridge/US
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Resources

Abstract 4023

Background

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.

Methods

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.

Results

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).

Conclusions

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.

Clinical trial identification

NA

Legal entity responsible for the study

Foundation Medicine

Funding

Foundation Medicine

Disclosure

All authors have declared no conflicts of interest.

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