AI Article Synopsis
- Establishing causal links between genetic variants and cancer risk is complicated, but this study highlights the single-nucleotide polymorphism rs55705857, which significantly increases the risk of low-grade glioma (LGG).
- The research identifies rs55705857 as the causal variant influencing molecular pathways related to LGG, specifically by disrupting OCT2/4 binding within a brain-specific enhancer, leading to greater gene expression.
- Animal experiments show that altering the corresponding mouse gene accelerated tumor development, demonstrating the variant's role in hereditary susceptibility to severe gliomas in approximately 40% of LGG patients.
Article Abstract
Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase (-mutant low-grade glioma (LGG). 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 promoter and increased expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an -driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9926876 | PMC |
| http://dx.doi.org/10.1126/science.abj2890 | DOI Listing |
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