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Team Untangles Mechanism Behind Noncoding Glioma Risk Variant

NEW YORK – Investigators at Mount Sinai Hospital, the University of Toronto, the Mayo Clinic, and other centers have characterized causal ties between a brain-specific enhancer variant and a form of low-grade glioma (LGG) involving isocitrate dehydrogenase (IDH) enzyme alterations.

"LGG are slow-growing brain tumors that eventually progress to aggressive glioblastoma," co-senior and co-corresponding authors Daniel Schramek, a researcher affiliated with Mount Sinai Hospital and the University of Toronto, and Mayo Clinic's Robert Jenkins, and their colleagues wrote in Science on Thursday, noting that IDH1/2 gene mutations typically turn up in some 70 percent of LGGs.

Following up on findings from past genome-wide association studies, the team set out to characterize a noncoding SNP on chromosome 8 known as rs55705857 that appears to boost the risk of IDH1-mutant LGG by roughly six times but does not seem to impact the risk of IDH1-wild type gliomas or other cancer types.

"[W]e sought to reveal the molecular underpinnings for the specific and strong association between rs55705857 and IDH-mutant LGG as a basis for understanding LGG initiation and heritable risk of developing glioma in [about 40 percent] of IDH1/2-mutant LGG patients carrying the rs55705857-G risk allele," the authors explained.

Using genotyping profiles for 622 individuals with IDH1-mutant LGG and 668 unaffected controls, the researchers teased apart recombination events related to the rs55705857-containing haplotype, weeding out alternative variants that were not found in all affected cases.

Bringing in ATAC-seq-based chromatin accessibility profiles, chromatin immunoprecipitation sequencing data, and expression quantitative trait locus analyses that involved dozens of IDH-mutant or IDH-wild type glioma tumors, meanwhile, the researchers pinned the IDH1-mutant glioma-related risk variant down to an enhancer that is active in brain tissue.

Based on these and other follow-up analyses, the researchers reported that the rs55705857 risk allele shifts MYC pathway activity by altering OCT2 and OCT4 transcription factor binding at the enhancer site, leading to more pronounced MYC promoter interactions.

"The region surrounding rs55705857 is clearly an area of increased enhancer activity specifically in IDH-mutant tumors," the authors wrote. "The hyperactive chromatin status, combined with the tissue specificity of this enhancer, thus explains the cooperativity between mutant IDH1/2 and rs55705857 and why rs55705857-G is associated specifically with IDH1/2-mutant glioma but not other brain cancers."

In IDH-mutant mice, for example, the team noted that changes at the rs55705857 site hastened tumor development, speeding it up to 172 days, on average, compared to an average of 472 days in mice with wild-type versions of rs55705857.

"Although several other germline SNPs are associated with the development of LGG, rs55705857 confers by far the greatest risk above and beyond combinations of the other LGG risk loci," the authors noted, adding that "we reveal a functional link between the rs55705857 germline variants, OCT-mediated regulation of MYC expression, and the development of IDH-mutant LGG."