Gene sequencing project discovers mutations tied to deadly brain tumors in young children

The investigators also identified alteration in NTRK genes that drove tumor development in young HGG patients whose tumors developed outside the brainstem. This study included 10 patients who were age 3 or younger when they were diagnosed with such non-brainstem HGGs. Of those, 40 percent 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, Ph.D., a member of the St. Jude Department of Developmental Neurobiology. The other corresponding author is Jinghui Zhang, Ph.D., a member of the St. Jude Department of Computational Biology. “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,” Baker said.

Added co-author Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis: "We’ve made some very exciting discoveries that likely will result in more effective diagnosis and treatment of these particularly nasty tumors.”

In this study, researchers analyzed 127 HGGs 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 DIPG patients was one of the biggest surprises, 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, or BMP. The pathway 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 DIPG resulted in the BMP pathway being inappropriately and permanently switched on.

In individuals with an inherited disorder called fibrodysplasia ossificans progressiva (FOP), the same ACVR1 mutations lead not to cancer, but to a different mechanism resulting in abnormal growth of bone in other tissues. Patients with FOP carry the ACVR1 mutation in every cell, while the gene is mutated only in the tumor cells of DIPG 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,” Baker said.

The ACVR1 mutations often occurred with mutations in a gene that carries instructions for making the histone H3.1 protein. That protein 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. Baker said the new findings suggest the two mutations work together to give tumor cells a selective advantage in the developing brainstem.

While the ACVR1 mutations occurred only in tumors in the brainstem, the NTRK fusion genes were found in HGGs 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 HGGs 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 HGGs. The NTRK fusion genes were identified in part through targeted sequencing of RNA. RNA molecules help translate the instructions carried in DNA into the proteins that do the work of cells. This study was the first to include RNA sequencing in an analysis of HGGs.

The study was part of the Pediatric Cancer Genome Project, which has sequenced the complete normal and tumor genomes of 700 young cancer patients. The project was launched in 2010 to harness advances in genome sequencing technology to improve understanding and treatment of some of the most aggressive and least understood childhood cancers.

The study’s first authors are Gang Wu and Alexander Diaz, both of St. Jude. The other authors are Barbara Paugh, Sherri Rankin, Bensheng Ju, Yongjin Li, Xiaoyan Zhu, Chunxu Qu, Xiang Chen, Junyuan Zhang, John Easton, Michael Edmonson, Xiaotu Ma, Panduka Nagahawatte, Erin Hedlund, Michael Rusch, Stanley Pounds, Tong Lin, Arzu Onar-Thomas, Robert Huether, Richard Kriwacki, Matthew Parker, Pankaj Gupta, Jared Becksfort, Heather Mulder, Kristy Boggs, Bhavin Vadodaria, Donald Yergeau, Frederick Boop, Alberto Broniscer, Cynthia Wetmore, Amar Gajjar, Michael Taylor, James Downing and David Ellison, all of St. Jude; Jake Russell, formerly of St. Jude; Charles Lu, Kerri Ochoa, Robert Fulton, Lucinda Fulton, Li Ding and Elaine Mardis, all of Washington University; Lei Wei of Roswell Park Cancer Institute, Buffalo, N.Y.; and Chris Jones of the Institute for Cancer Research, London.

The study was funded in part by the Pediatric Cancer Genome Project, including Kay Jewelers, a lead sponsor; grants (CA096832, CA135554) from the National Institutes of Health, The Cure Starts Now Foundation, Smile for Sophie Forever Foundation, Tyler’s Treehouse, Musicians Against Childhood Cancer and ALSAC.