Abstract
GFI1 and GFI1B can be activated by juxtaposition to active enhancers in Group 3 and 4 medulloblastoma.
Major finding: GFI1 and GFI1B can be activated by juxtaposition to active enhancers in Group 3 and 4 medulloblastoma.
Concept: Combined expression of GFI1 or GFI1B and MYC can drive medulloblastoma formation in mice.
Impact: Gene activation by rearrangements involving enhancer regions may be a common oncogenic mechanism.
Group 3 and Group 4 medulloblastomas are the most aggressive but least understood medulloblastoma subtypes. Northcott, Lee, Zichner, and colleagues evaluated all detectable chromosomal rearrangements identified by whole-genome sequencing of 137 Group 3 and 4 medulloblastomas and found that 6.6% of cases were distinguished by focal chromosome 9q34 rearrangements. Of the known genes in this region, only growth factor independent 1B (GFI1B) was differentially expressed, and analysis of 727 medulloblastomas showed that GFI1B overexpression was restricted to Group 3 and 4 tumors, with 10 of 11 GFI1B-overexpressing tumors in a validation set harboring 9q34 structural variants. Of note, these rearrangements did not directly affect the GFI1B coding region, but resulted in juxtaposition of GFI1B to noncoding DNA elements normally hundreds of kilobases upstream, suggesting that “hijacking” of enhancer regulatory elements might activate GFI1B. Indeed, chromatin immunoprecipitation sequencing for enhancer-associated histone marks revealed clusters of highly active enhancers, or super-enhancers, overlapping or adjacent to chromosomal breakpoints in GFI1B-overexpressing cases. The GFI1B paralog GFI1 was also found to be specifically overexpressed in Group 3 and Group 4 medulloblastomas and similarly rearranged such that the GFI1 locus becomes proximal to super-enhancers. Overall, mutually exclusive GFI1 or GFI1B activation was observed in 41% of Group 3 tumors and 10% of Group 4 tumors. Neither GFI1, GFI1B, nor MYC expression alone was sufficient to drive transformation of neural stem cells implanted into murine cerebella, but the combination of either GFI family member and MYC drove the rapid formation of aggressive cerebellar tumors that recapitulated features of human Group 3 tumors. In addition to identifying enhancer-driven GFI1 and GFI1B activation as one of the most prevalent driving events in Group 3 and 4 medulloblastomas, these findings suggest that existing cancer sequencing data should be evaluated beyond minimal common regions of amplification or deletion to identify oncogenic mechanisms of gene deregulation.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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