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Genotyping/Sequencing Combination Identifies Glioma Risk Variant with Possible miRNA Role

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A study published in Nature Genetics last month has identified a genetic variant strongly associated with higher risk of certain brain tumors, and suggests the involvement of a long non-coding RNA or a microRNA.

According to the study, which was led by researchers from the Mayo Clinic and the University of California, San Francisco, the variant is located at 8q24.21 and is strongly associated with higher risk of a subset of glioma brain tumors, specifically those with IDH1 or IDH2 mutations.

Though the function of the locus is not known definitively, structural modeling of the risk region has indicated that it might encode either a novel lncRNA or miRNA, the group reported.

The researchers are continuing to study the risk locus to narrow down its biological function and how it might influence mutations in the IDH gene or interact with the downstream effects of such mutations to allow the development and progression of these cancers.

Robert Jenkins, the study's first author and a Mayo Clinic pathologist, told Gene Silencing News that it's still unclear whether the variant, a SNP dubbed rs55705857, codes for a miRNA. But, he said, the fact that the risk locus is so strongly and specifically associated with IDH mutated gliomas suggests it may play some role in the "gene silencing" phenotype of these tumors.

"This particular variant is very low frequency in the population, about four percent, but it's associated with this specific subclass of gliomas that tend to have what you could call a gene silencing or methylating phenotype," Jenkins said.

"These tumors tend to acquire mutations in the genes IDH1 and IDH2,” he added. “One of the side effects of those mutations is that DNA gets methylated and histones get modified, so clearly there is some change in genomic structure and gene expression when that mutation happens."

Whether the variant the group identified in the study is a miRNA, part of a lncRNA that is also involved in gene silencing, or neither, "for some reason it's basically only found in tumors that acquire this phenotype, so that's interesting,” Jenkins said.

Jenkins said his team has been involved in genome-wide association studies of glioma, but so far, like many GWAS efforts, the approach has not turned up loci with strong risk associations. So the group decided to look more deeply, with a combined genotyping and next-generation sequencing approach, to see if they could find a stronger risk locus in a promising region from their earlier studies.

"The two choices, which are not mutually exclusive, are that the common variants GWAS studies identify actually change people's risk, or that [these common variants don't influence risk themselves, but] are associated with other low-frequency variants that [do have] functional value, and they just go along for the ride," he said.

"We made the assumption that it was the latter – and we got lucky," Jenkins said.

In the study, Jenkins' team and UCSF collaborators examined a total of 1,657 cases and 1,301 controls split into two approximately equal groups — one at each institution.

The team used a two-stage approach, starting with long-range PCR and pooled next-generation sequencing, and then validated its results using a custom genotyping approach. After stratifying cases by glioma subtype, the group identified seven SNPs with significant glioma risk associations.

The strongest association, measured by odds ratio, belonged to the G allele of the rs55705857 SNP, which showed an OR of 6.3 among the oligodendroglioma cases, and similar associations with IDH-mutated glioblastomas and astrocytomas, the group reported.

Approximately 40 percent of subjects with these glioma subtypes carry one or more of the G risk alleles for rs557058576 compared to only 8 percent of controls, the authors wrote.

While all seven of the SNPs the group found were associated with some risk, only rs55705857 remained significant after individually adjusting for the remaining six.

The researchers wrote in their report that risk associations as strong as this one have "rarely been reported in cancer genome-wide association and subsequent fine mapping studies."

In the paper, the group reported that structural modeling suggests the locus might encode a novel lncRNA or miRNA. However, the actual functional role of the region is not yet known.

Jenkins said his team is now in the process of determining whether the variant really is a miRNA or an lncRNA.

The group is also planning to test its hypothesis that rs55705857 and IDH mutations interact in some way to produce the types of tumors the variant is associated with.

"Because of the observation that it seems to be found in these tumors with a methylator phenotype, we want to see if we can model the development of such tumors by making mice that have IDH mutations as well as this SNP," he said.

"We would predict that together, they would create tumors that have this methylator phenotype."

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