Isoform-level gene signature improves prognostic stratification and accurately classifies glioblastoma subtypes

Sharmistha Pal, Yingtao Bi, Luke MacYszyn, Louise C. Showe, Donald M. O'Rourke, Ramana V. Davuluri*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Molecular stratification of tumors is essential for developing personalized therapies. Although patient stratification strategies have been successful; computational methods to accurately translate the gene-signature from high-throughput platform to a clinically adaptable low-dimensional platform are currently lacking. Here, we describe PIGExClass (platform-independent isoform-level gene-expression based classification-system), a novel computational approach to derive and then transfer gene-signatures from one analytical platform to another. We applied PIGExClass to design a reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) based molecular-subtyping assay for glioblastoma multiforme (GBM), the most aggressive primary brain tumors. Unsupervised clustering of TCGA (the Cancer Genome Altas Consortium) GBM samples, based on isoform-level gene-expression profiles, recaptured the four known molecular subgroups but switched the subtype for 19% of the samples, resulting in significant (P = 0.0103) survival differences among the refined subgroups. PIGExClass derived four-class classifier, which requires only 121 transcript-variants, assigns GBM patients' molecular subtype with 92% accuracy. This classifier was translated to an RT-qPCR assay and validated in an independent cohort of 206 GBM samples. Our results demonstrate the efficacy of PIGExClass in the design of clinically adaptable molecular subtyping assay and have implications for developing robust diagnostic assays for cancer patient stratification.

Original languageEnglish (US)
Pages (from-to)e64
JournalNucleic acids research
Volume42
Issue number8
DOIs
StatePublished - Apr 2014

Funding

The authors thank Drs. Michael Showe and Nadia Dahmane for many helpful suggestions in editing of the manuscript. The use of resources in the Genomics Shared Facility of Wistar Cancer Centre [P30 CA010815] is gratefully acknowledged. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. R.D. holds a Philadelphia Healthcare Trust Endowed Chair Position; research in his laboratory is partially supported by the Philadelphia Healthcare Trust.

ASJC Scopus subject areas

  • Genetics

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