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Structural Variant Study Points to Pediatric Glioma Drivers, Prognostic Features

NEW YORK – A team led by researchers at Harvard University has identified structural variants (SVs) that appear to coincide with tumor development or clinical outcomes in children with pediatric high-grade glioma.

"These data provide insight into the impact of SVs on gliomagenesis and the mechanisms that shape them," senior authors Pratiti Bandopadhayay, Rameen Beroukhim, and Keith Ligon, researchers affiliated with the Broad Institute, Harvard, and Dana-Farber, and their colleagues wrote in Nature Cancer on Monday. "We identified recurrent driver events, stratified [pediatric high-grade gliomas] based upon mechanistically informative SV signatures, and detected genetic events and differences in clinical outcomes associated with these signatures."

Using whole-genome sequencing, the researchers searched for recurrent SV and somatic copy number changes in 179 pediatric glioma cases, uncovering SVs falling in or around known cancer-related genes in all but three of the tumors. Their results suggested that specific genes such as MYC or genes coding for receptor tyrosine kinase enzymes are particularly susceptible to the impact of recurrent SVs, though the precise mutation signature at play varied depending on the pediatric high-grade glioma subtype.

The team noted that tandem duplications in the enhancer region of MYC were detected in a subset of diffuse midline gliomas (DMGs), for example. Those MYC enhancer amplifications turned up in more than 10 percent of the DMG tumors analyzed.

"The MYC enhancer amplifications highlight an underrecognized role for MYC in [pediatric high-grade gliomas]," the authors reported, adding that "the role of MYC in [pediatric high-grade glioma] formation requires further study."

Sequence analyses also led to recurrent alterations affecting components of the TP53 pathway in tumors with wild-type TP53, as well as in tumors with direct changes in TP53 and other genes such as CDKN2A and RB1, the researchers reported.

While tumors with wild-type TP53 tended to have relatively simple mutation signatures, SVs in TP53, CDKN2A, and RB1 appeared to arise early on in the tumor development process and corresponded to more complex mutation signatures marked by extrachromosomal amplifications that turned up at later stages of tumor evolution.

The team noted that the complex signature was overrepresented in DMG subtype tumors carrying H3.3 histone mutations and in pediatric high-grade glioma tumors from the hemispheric subtype. Compared to the simple signatures, which were documented in all of the tumors tested, the complex signatures corresponded to shorter overall survival times regardless of the specific histone alterations identified or the presence or absence of TP53 mutations.

"The association between the complex SV signatures and survival might be causative and indicate potential therapeutic targets, or it could represent a quantifiable biomarker for underlying factors such as genome instability," the authors noted.

More broadly, the authors suggested that findings from the current study "indicate that both research and clinical sequencing of these tumors should encompass the whole genome."