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Study Points to Key Driver Fusion in Pediatric Angiocentric Glioma

NEW YORK (GenomeWeb) – An international team led by investigators at the Dana-Farber Cancer Institute and the Children's Hospital of Philadelphia has detected a gene fusion that contributes to the development of a form of pediatric low-grade glioma called angiocentric glioma through three distinct mechanisms.

Using genome and/or RNA sequence data for hundreds of new and previously assessed pediatric low-grade glioma samples, the researchers uncovered a candidate driver fusion for angiocentric glioma involving the MYB and QKI genes — a rearrangement they subsequently scrutinized with in vitro and in vivo experiments.

Their findings, published online today in Nature Genetics, suggest this rearrangement nudges along angiocentric glioma development by activating the MYB gene, knocking out one copy of the tumor suppression gene QKI, and translocating promoter sequences that boost expression of the fusion.

"Now that we better understand the three mechanisms involved, we may be better able to craft our treatment strategies against any of those mechanisms," co-senior author Adam Resnick, a neuro-oncology researcher at the Children's Hospital of Philadelphia, said in a statement.

To boost their ability to find recurrent alterations in pediatric low-grade glioma subtypes, the study's authors analyzed whole-genome sequence and/or RNA sequencing data for 145 published pediatric low-grade glioma samples and 27 new samples spanning 10 histological subtypes.

Along with recurrent somatic glitches, which the team detected in 90 percent of the tumor samples, the search unearthed rearrangements or structural changes in 129 of the tumors — just over 80 percent.

In particular, the researchers found that nearly 10 percent of the pediatric low-grade glioma tumors — most from the diffuse astrocytoma or angiocentric glioma subtypes — contained rearrangements centered on MYB family genes such as MYB and MYBL1.

Moreover, the MYB gene seemed especially prone to melding with QKI in angiocentric glioma tumors, prompting the team to search for the fusion in a dozen more formalin-fixed, paraffin-embedded angiocentric glioma samples.

Indeed, MYB alterations appeared in all 12 of the angiocentric gliomas, which were assessed using fluorescence in situ hybridization, whole-exome sequencing, and/or array comparative genomic hybridization, the researchers reported. And MYB changes were consistently found across the broader set of 19 angiocentric glioma samples tested, often involving fusions to QKI.

In contrast, the team did not detect MYB-QKI fusions in non-angiocentric glioma samples from the original pediatric low-grade glioma tumor set. In another 65 non-angiocentric glioma samples, a single MYB alteration-positive tumor turned up.

The researchers attempted to predict the functional consequences of the recurrent MYB-QKI fusion with a series of follow-up analyses using available expression data, developing mouse embryo and mouse neural stem cell experiments, and other approaches.

Their results hinted that the MYB-QKI fusion could be a key driver event in angiocentric glioma, leading to a three-pronged risk of the disease due to a loss of tumor suppressor activity by QKI, enhancer element translocation, and oncogenic activity by the fusion itself. 

"We propose that the presence of this fusion should be considered diagnostic for angiocentric glioma," Resnick and co-authors wrote. "This could aid in distinguishing angiocentric gliomas from tumors with higher potential for recurrence or that require further treatment, such as IDH-mutant diffuse gliomas or ependymomas."