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Series GSE206875 Query DataSets for GSE206875
Status Public on Sep 12, 2022
Title A non-coding single nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation
Organisms Homo sapiens; Mus musculus
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single nucleotide polymorphism rs55705857 (A>G), which confers a 6-fold increased risk of IDH-mutant low-grade glioma (LGG) and is amongst the highest genetic associations with cancer. By fine-mapping the locus, we reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. To functionally test rs55705857, we generated an IDH1R132H-driven LGG mouse model and show that mutating the highly conserved, orthologous mouse rs55705857 locus dramatically accelerated tumor development from 463 to 172 days and increased penetrance from 30% to 75%. Overall, our work generates new LGG models and reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG-patients.
Overall design RNA Seq, ChIP seq, Genomic interactions
Contributor(s) Yanchus C, Malik A, Schramek D
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Submission date Jun 24, 2022
Last update date Nov 29, 2022
Contact name Daniel Schramek
Organization name Lunenfeld- Tanenbaum Research Institute
Lab Schramek Lab
Street address 600 University Ave, Room 1080
City Toronto
State/province ON
ZIP/Postal code M5G 1X5
Country Canada
Platforms (3)
GPL21493 Illumina HiSeq 3000 (Mus musculus)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (24)
GSM5253946 Neural progenitor cells - rs557 A/A- myc
GSM5253947 Neural progenitor cells - rs557 A/G- myc
GSM5253948 cohort I 205
This SuperSeries is composed of the following SubSeries:
GSE172390 Genomic interactions of Myc and rs55705857 in primary mouse derived neural stem cells
GSE172391 RNA seq of mouse low grade glioma tumors
GSE206873 Glioma MYC gene signature
BioProject PRJNA852543

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Supplementary file Size Download File type/resource
GSE206875_RAW.tar 11.7 Mb (http)(custom) TAR (of NARROWPEAK, ZIP)
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