Gene Sequencing Project Discovers Mutations Tied to High-Grade Gliomas in Young Children
The St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project has identified new mutations in pediatric high-grade gliomas. The findings by Wu et al were published in Nature Genetics and may lead to improved outcomes for children with these brain tumors, particular the youngest patients.
Genomic Landscape of High-Grade Glioma
The discoveries stem from the most comprehensive effort yet to identify the genetic missteps driving these deadly tumors. The results provide much-needed drug development leads, particularly for agents that target the underlying mutations. This and other studies show these mutations often differ based on patient age. High-grade gliomas represent 15% to 20% of brain and spinal tumors in children. Despite aggressive therapy with surgery, radiation, and chemotherapy, long-term survival for high-grade glioma patients remains less than 20%.
The study is one of four being published simultaneously in the same issue of Nature Genetics that link recurring mutations in ACVR1 to cancer for the first time. Pediatric Cancer Genome Project researchers found that ACVR1 was mutated in 32% of 57 patients diagnosed with a subtype of high-grade glioma called diffuse intrinsic pontine glioma. While diffuse intrinsic pontine glioma are usually found in children aged 5 to 10, ACVR1 mutations occurred most frequently in younger-than-average patients. Diffuse intrinsic pontine glioma occurs in the brainstem, which controls vital functions and cannot be surgically removed.
The investigators also identified alteration in NTRK genes that drove tumor development in young high-grade glioma patients whose tumors developed outside the brainstem. This study included 10 patients who were aged 3 or younger when they were diagnosed with such nonbrainstem high-grade gliomas. Of those, 40% had tumors with alterations in one of three NTRK genes and few other changes. The alterations occurred when a segment of the NTRK genes involved in regulating cell division fused with part of another gene.
“These results indicate the NTRK fusion genes might be very potent drivers of cancer development that have the ability to generate tumors with few other mutations,” said co-corresponding author Suzanne Baker, PhD, a member of the St. Jude Department of Developmental Neurobiology. “We want to see if these tumors might be selectively sensitive to therapies that target the pathways that are disrupted as a result of these fusion genes,” she said.
Coauthor Richard K. Wilson, PhD, Director of The Genome Institute at Washington University School of Medicine in St. Louis, added, "We’ve made some very exciting discoveries that likely will result in more effective diagnosis and treatment of these particularly nasty tumors.”
ACVR1 Mutations
In this study, researchers analyzed 127 high-grade gliomas from 118 pediatric patients, including whole-genome sequencing of the complete tumor and normal DNA from 42 patients. More targeted sequencing of additional tumors was conducted to track how instructions encoded in DNA were translated into the proteins that do the work of cells.
The recurring presence of ACVR1 mutations in a subset of diffuse intrinsic pontine glioma patients was one of the biggest surprises, Dr. Baker said. ACVR1 carries instructions for making a protein receptor on the cell membrane. The receptor functions as an on-off switch for a biochemical pathway named bone morphogenetic protein (BMP), which helps regulate growth and development of bone and other tissue. Working in zebra fish and mouse brain cells, researchers found evidence that ACVR1 mutations from diffuse intrinsic pontine glioma resulted in the BMP pathway being inappropriately and permanently switched on.
In individuals with an inherited disorder called fibrodysplasia ossificans progressiva, the same ACVR1 mutations lead not to cancer, but to a different mechanism resulting in abnormal growth of bone in other tissues. Patients with fibrodysplasia ossificans progressiva carry the ACVR1 mutation in every cell, while the gene is mutated only in the tumor cells of diffuse intrinsic pontine glioma patients.
“The same mutations are doing something very different in these two terrible and rare diseases. We are working to understand not only how the mutations contribute to cancer, but also whether blocking the BMP pathway offers a new way to treat the tumor,” Dr. Baker said.
The ACVR1 mutations often occurred with mutations in a gene that carries instructions for making the histone H3.1 protein, which influences gene activity through its role in packaging DNA in the nucleus. Mutations in the histone H3 family of proteins were first reported in an earlier Pediatric Cancer Genome Project study. Dr. Baker said the new findings suggest the two mutations work together to give tumor cells a selective advantage in the developing brainstem.
NTRK Fusion Gene
While the ACVR1 mutations occurred only in tumors in the brainstem, the NTRK fusion genes were found in high-grade gliomas that developed throughout the brain. By combining pieces of different genes, fusion genes can lead to production of abnormal proteins that disrupt cell function. Fusion genes were identified in almost half of all pediatric high-grade gliomas in this study, but the NTRK fusions were the most common. The NTRK fusions involved a gene segment encoding a tyrosine kinase domain. This domain functions as an on-off switch for several important regulatory mechanisms in cells that often malfunction in cancer cells.
NTRK fusion genes have been identified in other pediatric and adult brain tumors. This study marks the first report of the genes in pediatric high-grade gliomas. The NTRK fusion genes were identified in part through targeted sequencing of RNA.
Dr. Baker and Jinghui Zhang, PhD, of St. Jude Department of Computational Biology, are the corresponding authors for the Nature Genetics article.
The study was funded in part by the Pediatric Cancer Genome Project, the National Institutes of Health, The Cure Starts Now Foundation, Smile for Sophie Forever Foundation, Tyler’s Treehouse, Musicians Against Childhood Cancer, and ALSAC.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
