NEW YORK – An international team led by investigators at Toronto's Hospital for Sick Children (Sick Kids) has documented genetic alterations in a brain tumor subtype called pediatric low-grade glioma (pLGG) that correspond with better or worse patient outcomes.
By bringing together imaging, histology, targeted DNA sequencing, RNA sequencing, clinical, and other data for more than 1,000 children with pLGG, the researchers narrowed in on two broad groups of tumors marked either by recurrent rearrangements or by single-nucleotide variants. Broadly speaking, they noted, rearrangement-rich tumors tended to turn up in relatively low-risk pLGG cases, while certain sets of single-nucleotide changes coincided with intermediate- or high-risk pLGG cases.
The "[pLGG morphological, imaging, clinical, and molecular profiling] allowed us to comprehensively investigate the molecular underpinnings and provide comprehensive clinical insights for some of the rarest of pLGG molecular subtypes," co-senior and corresponding author Cynthia Hawkins, a researcher affiliated with Sick Kids and the University of Toronto, and her co-authors wrote in a paper published in Cancer Cell on Monday.
"These data can guide diagnostic protocols and treatment approaches," they added, "while aiding in expediting clinical trials for new, better-targeted therapies for these children in the near future," they wrote.
Starting with data for 976 pLGG patients treated at Sick Kids between the mid-1980s and 2017, Hawkins and her colleagues focused in on 477 cases that could be successfully profiled using methods such as RNA-seq, NanoString nCounter analyses, array-based SNP profiling, targeted DNA sequencing, droplet digital PCR, and immunohistochemistry.
Roughly two-thirds of the cases contained BRAF or NF1 mutations, or KIAA1549-BRAF fusions, the researchers reported, with some 84 percent of pLGG tumors containing mutations in a known driver gene. Moreover, enhanced RAS/MAPK activity appeared in many tumors without clear driver mutations.
The team also drew prognostic insights from the kinds of mutations that occurred often in the pLGGs. For example, a cluster of 265 tumors appeared to have rearrangement-related drivers. Those tumors were overrepresented in children diagnosed with pLGG before the age of 10, the investigators noted, and some 88 percent were classified as having grade I histology. In those rearrangement-related cases, the 10-year overall survival rate reached nearly 98 percent.
On the other hand, more than half of the 182 tumors marked by single nucleotide variants occurred in children diagnosed later, after their 10th birthdays, the researchers reported. Roughly one-third of those tumors had grade II histology, they found, and the 10-year overall survival rate dipped to 88 percent in this group of pLGG patients.
The team saw similar patterns when it extended its analyses to include 61 more pLGG patients with rare tumor alterations who had been profiled at centers in the US, including the St. Jude Children's Research Hospital, the Children's Hospital of Philadelphia, and Memorial Sloan Kettering Cancer Center.
Together, the authors noted, "this comprehensive molecular landscape of the clinical and molecular features of pLGG provides clinicians with an invaluable resource for the management of common and rare molecular pLGG subtypes."