Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma
By P. Northcott, Catherine Lee, T. Zichner, A. Stütz, S. Erkek, D. Kawauchi, D. Shih, V. Hovestadt, M. Zapatka, D. Sturm and 69 more. Nature, 2014
614 citations recorded by the source corpus.
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.
Subfields: Genetics, Neurology
View Paper: https://www.semanticscholar.org/paper/0f8d3aa8b8b983b6a633d9f11dd1ea47402a2e30
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Citations in the corpus
- Transcriptional Addiction in Cancer (2017, neutral): “The genetic mechanisms that lead to SE acquisition in cancer include DNA translocation (Affer et al., 2014; Drier et al., 2016; Groschel et al., 2014; Northcott et al., 2014; Walker et al., 2014), focal amplification (Hnisz et al.”
- The landscape of genomic alterations across childhood cancers (2018, neutral): “As evidenced by recurrent structural variation outside genes (based on breakpoint clusters in 10-kb windows), rearrangements linked to enhancer hijacking were also found, involving GFI1B and DDX31 in medulloblastomas and TERT in neuroblastomas 40,41 .”
- Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma (2017, background): “…in tumors of all locations and all subgroups (Figure S3B), and gains of 9q (n = 108), more broadly encompassing a region of structural rearrangement on 9q34 in medulloblastoma (Northcott et al., 2014), and correlating with shorter overall survival in multiple pHGG/DIPG subgroups (Figure S3C).”
- The whole-genome landscape of medulloblastoma subtypes (2017, neutral): “In the coding space and as expected, several known and presumed MB driver genes were revealed in our series, including PTCH1 , DDX3X , KMT2D (formerly known as MLL2 ) and others, many of which showed clear subgroup-specificity (Fig.”
- Regulation of disease-associated gene expression in the 3D genome (2016, neutral): “This phenomenon is what occurs in enhancer hijacking 118 .”