Rare inherited variants shape risk and outcomes in pediatric brain and spinal cord tumors

Researchers at Children's Hospital of Philadelphia (CHOP) and Children's National Hospital in Washington D.C. are uncovering how rare inherited genetic variants contribute to the development of brain and spinal cord tumors in children. The findings, published in the journal Nature Communications, provide new insights into how a child's genetic makeup influences cancer risk and outcomes.

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. While up to one in four children with cancer carry rare genetic variants that increase cancer risk, the specific genetic drivers of pediatric CNS tumors remain poorly understood.

In this study, investigators from CHOP, Children's National, and collaborating institutions examined how pathogenic (P) and likely pathogenic (LP) germline variants influence tumor risk, biology, and patient outcomes in children with CNS tumors. Pathogenic variants are known to increase disease risk, while likely pathogenic variants are suspected to do so but lack definitive evidence.

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. By understanding these risk factors and patterns, we move closer to developing more personalized, effective care for children with CNS tumors." 

Sharon J. Diskin, PhD, senior author of the study and principal investigator at CHOP's Center for Childhood Cancer Research

The team analyzed blood and tumor samples from 830 children with brain or spinal cord tumors from the Pediatric Brain Tumor Atlas. By studying the DNA and other molecular features of the tumors, they looked for genetic changes present from birth - either inherited from parents or newly occurring in the child - that might make some children more likely to develop these cancers. The team then compared these changes to each child's medical record to determine whether known tumor predisposition syndromes had been previously identified.

They found that nearly one in four children (23.3%) carried a genetic change in a gene known to increase cancer risk. Among all patients, 7% (57 children) had already been diagnosed with a known genetic condition linked to tumor development, while another 6% (48 children) harbored genetic changes in CNS tumor-associated genes that had not yet been clinically recognized. These findings highlight that many inherited or early arising genetic risks remain undetected in current practice, emphasizing the need for comprehensive genetic screening for children with brain and spinal cord tumors.

The researchers also discovered that 35% of children with these genetic variants had additional changes in the same genes within their tumors, leading to loss of normal gene function. This pattern supports the "two hit" model of cancer development – where one genetic alteration is inherited and a second arises in the tumor – showing how inherited risk shapes tumor biology and 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 a principal investigator at Children's National's Brain Tumor Institute and Center for Cancer and Immunology Research. "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."

This work was funded in part by National Institutes of Health (NIH) grants 03CA287169, R03OD036498, U24OD038422, R03CA230366, the NIH Kids First Cloud Credits Program, the Children's Brain Tumor Network, the Chad Tough Foundation, and the anonymous private investors to the Children's National Hospital Brain Tumor Institute.