Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma

Michele Ceccarelli, Floris P. Barthel, Tathiane M. Malta, Thais S. Sabedot, Sofie R. Salama, Bradley A. Murray, Olena Morozova, Yulia Newton, Amie Radenbaugh, Stefano M. Pagnotta, Samreen Anjum, Jiguang Wang, Ganiraju Manyam, Pietro Zoppoli, Shiyun Ling, Arjun A. Rao, Mia Grifford, Andrew D. Cherniack, Hailei Zhang, Laila PoissonCarlos Gilberto Carlotti, Daniela Pretti Da Cunha Tirapelli, Arvind Rao, Tom Mikkelsen, Ching C. Lau, W. K.Alfred Yung, Raul Rabadan, Jason Huse, Daniel J. Brat, Norman L. Lehman, Jill S. Barnholtz-Sloan, Siyuan Zheng, Kenneth Hess, Ganesh Rao, Matthew Meyerson, Rameen Beroukhim, Lee Cooper, Rehan Akbani, Margaret Wrensch, David Haussler, Kenneth D. Aldape, Peter W. Laird, David H. Gutmann, Houtan Noushmehr*, Antonio Iavarone, Roel G.W. Verhaak, TCGA Research Network

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

791 Scopus citations

Abstract

Summary Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes.

Original languageEnglish (US)
Pages (from-to)550-563
Number of pages14
JournalCell
Volume164
Issue number3
DOIs
StatePublished - Jan 28 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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