|
| 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
Other
|
| 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.
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| Overall design |
RNA Seq, ChIP seq, Genomic interactions
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| |
|
| Contributor(s) |
Yanchus C, Malik A, Schramek D |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Jun 24, 2022 |
| Last update date |
Nov 29, 2022 |
| Contact name |
Daniel Schramek |
| E-mail(s) |
schramek@lunenfeld.ca
|
| 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)
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| 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 |
|
| Relations |
| BioProject |
PRJNA852543 |
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