Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma

Sturm, Dominik and Witt, Hendrik and Hovestadt, Volker and Khuong-Quang, Dong-Anh and Jones, David T W and Hauser, Peter and Garami, Miklos and Klekner, Almos and Bognar, Laszlo (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer cell, 22 (4). pp. 425-437. ISSN 1878-3686

Text Hotspot Mutations in H3F3A and IDH1 Define Distinct Epigenetic and Biological Subgroups of Glioblastoma.pdf Restricted to Registered users only Download (2MB) | Request a copy

Abstract

Glioblastoma (GBM) is a brain tumor that carries a dismal prognosis and displays considerable heterogeneity. We have recently identified recurrent H3F3A mutations affecting two critical amino acids (K27 and G34) of histone H3.3 in one-third of pediatric GBM. Here, we show that each H3F3A mutation defines an epigenetic subgroup of GBM with a distinct global methylation pattern, and that they are mutually exclusive with IDH1 mutations, which characterize a third mutation-defined subgroup. Three further epigenetic subgroups were enriched for hallmark genetic events of adult GBM and/or established transcriptomic signatures. We also demonstrate that the two H3F3A mutations give rise to GBMs in separate anatomic compartments, with differential regulation of transcription factors OLIG1, OLIG2, and FOXG1, possibly reflecting different cellular origins.

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