Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.

Journal: 
Nature
Publication Year: 
2014
Authors: 
Paul A Northcott
Catherine Lee
Thomas Zichner
Adrian M Stutz
Serap Erkek
Daisuke Kawauchi
David J H Shih
Volker Hovestadt
Marc Zapatka
Dominik Sturm
David T W Jones
Marcel Kool
Marc Remke
Florence M G Cavalli
Scott Zuyderduyn
Gary D Bader
Scott VandenBerg
Lourdes Adriana Esparza
Marina Ryzhova
Wei Wang
Andrea Wittmann
Sebastian Stark
Laura Sieber
Huriye Seker-Cin
Linda Linke
Fabian Kratochwil
Natalie Jager
Ivo Buchhalter
Charles D Imbusch
Gideon Zipprich
Benjamin Raeder
Sabine Schmidt
Nicolle Diessl
Stephan Wolf
Stefan Wiemann
Benedikt Brors
Chris Lawerenz
Jurgen Eils
Hans-Jorg Warnatz
Thomas Risch
Marie-Laure Yaspo
Ursula D Weber
Cynthia C Bartholomae
Christof von Kalle
Eszter Turanyi
Peter Hauser
Emma Sanden
Anna Darabi
Peter Siesjo
Jaroslav Sterba
Karel Zitterbart
David Sumerauer
Peter van Sluis
Rogier Versteeg
Richard Volckmann
Jan Koster
Martin U Schuhmann
Martin Ebinger
H Leighton Grimes
Giles W Robinson
Amar Gajjar
Martin Mynarek
Katja von Hoff
Stefan Rutkowski
Torsten Pietsch
Wolfram Scheurlen
Jorg Felsberg
Guido Reifenberger
Andreas E Kulozik
Andreas von Deimling
Olaf Witt
Roland Eils
Richard J Gilbertson
Andrey Korshunov
Michael D Taylor
Peter Lichter
Jan O Korbel
Robert J Wechsler-Reya
Stefan M Pfister
PubMed link: 
25043047
Public Summary: 
Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
Scientific Abstract: 
Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.