New insights into genetics of childhood brain and spinal tumors

Researchers at Children’s National Hospital in Washington, D.C. and Children’s Hospital of Philadelphia (CHOP), are advancing understanding of how rare inherited genetic variants contribute to the development of brain and spinal cord tumors in children. The new findings, published in Nature Communications, reveal how a child’s genetic makeup can shape cancer risk, tumor behavior, and potentially long-term outcomes.

“We are currently expanding our study to include parental sequencing and more than doubling the number of patients,” said Jo Lynne Rokita, PhD, co-senior study author and  principal investigator at the Brain Tumor Institute and Center for Cancer and Immunology Research of Children’s National. “This will help us better understand how inherited or early arising genetic changes interact with those that develop in the tumor, ultimately improving how we diagnose, monitor and treat children with brain and spinal cord cancers.”

Cancers of the central nervous system (CNS) are the leading cause of cancer-related deaths in children, with more than 47,000 children and young adults diagnosed each year. Up to one in four children with cancer carry rare genetic variants that increase susceptibility, yet the mechanisms of inherited drivers of pediatric CNS tumors have remained poorly understood.

In this study, investigators from Children’s National, CHOP, and collaborating partners analyzed blood and tumor samples from 830 children with brain and spinal cord tumors using data from the Pediatric Brain Tumor Atlas. They looked for genetic changes present from birth — either inherited or newly occurring — that may predispose children to these cancers and compared those findings with each child’s medical history to identify known or previously unrecognized tumor predisposition syndromes.

“Our research provides a foundation for identifying patients whose genetic profiles influence both cancer susceptibility and how their disease behaves — in some cases signaling a higher risk for aggressive tumors, and in others, a better chance of survival,” said Sharon J. Diskin, PhD, senior author of the study and principal investigator at CHOP’s Center for Childhood Cancer Research. “By understanding these risk factors and patterns, we move closer to developing more personalized, effective care for children with CNS tumors.”

Researchers examined how pathogenic (P) and likely pathogenic (LP) germline variants influence tumor risk and clinical outcomes. Pathogenic variants are known to increase disease risk, while likely pathogenic variants are suspected but lack definitive evidence. Nearly one in four children (23.3%) carried a genetic change in a cancer-risk gene. Seven percent (57 children) had already been diagnosed with a genetic condition associated with tumor development, while another 6% (48 children) harbored cancer risk variants that had not yet been clinically recognized. These results underscore the need for more comprehensive genetic screening in pediatric CNS cancers, as many inherited or early-arising risks continue to go undetected.

The study also found that 35% of children with these variants had additional alterations in the same genes within their tumors, supporting the “two-hit” model of cancer development, where an inherited genetic change is followed by a second, tumor-specific event that drives cancer growth.

This work was supported in part by grants from the National Institutes of Health (NIH), the NIH Kids First Cloud Credits Program, the Children’s Brain Tumor Network, the Chad Tough Foundation and private donors to the Children’s National Hospital Brain Tumor Institute.

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