Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma
Menée sur des échantillons tumoraux prélevés sur plusieurs cohortes de patients pédiatriques atteints d'un médulloblastome, puis à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels les gènes GFI1 et GFI1B exercent une fonction d'oncogène
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.