Hotspot Mutations in H3F3A and IDH1 Define Distinct Epigenetic and Biological Subgroups of Glioblastoma

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• 作者：Dominik Sturm ; Hendrik Witt ; Volker Hovestadt ; Dong-Anh Khuong-Quang ; David?T.W. Jones ; Carolin Konermann ; Elke Pfaff ; Martje T?njes ; Martin Sill ; Sebastian Bender ; Marcel Kool ; Marc Zapatka ; Natalia Becker ; Manuela Zucknick ; Thomas Hielscher ; Xiao-Yang Liu ; Adam?M. Fontebasso ; Marina Ryzhova ; Steffen Albrecht ; Karine Jacob ; et al.
• 刊名：Cancer Cell
• 出版年：2012
• 出版时间：16 October, 2012
• 年：2012
• 卷：22
• 期：4
• 页码：425-437
• 全文大小：2250 K

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Summary

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.