Researchers studying a rare, lethal childhood tumor of thebrainstem discovered that nearly 80 percent of the tumors have mutations ingenes not previously tied to cancer. Early evidence suggests the alterationsplay a unique role in other aggressive pediatric brain tumors as well.
The findings from the St. Jude Children’s Research Hospital– Washington University Pediatric Cancer Genome Project (PCGP) offer importantinsight into a poorly understood tumor that kills more than 90 percent ofpatients within two years. The tumor, diffuse intrinsic pontine glioma (DIPG),is found almost exclusively in children and accounts for 10 percent to 15 percent ofpediatric tumors of the brain and central nervous system.
“We are hopeful that identifying these mutations will leadus to new selective therapeutic targets, which are particularly important sincethis tumor cannot be treated surgically and still lacks effective therapies,” saysSuzanne Baker, PhD, co-leader of the St. Jude Neurobiology and Brain TumorProgram and a member of the St. Jude Department of Developmental Neurobiology.She is a corresponding author of the study published in the Jan. 29 online editionof the journal Nature Genetics.
DIPG is an extremely invasive tumor that occurs in thebrainstem, which is at the base of the skull and controls such vital functionsas breathing and heart rate. DIPG cannot be cured by surgery and is accuratelydiagnosed by non-invasive imaging. As a result, DIPG is rarely biopsied in theUnited States, and little is known about it.
Cancer occurs when normal gene activity is disrupted,allowing for the unchecked cell growth and spread that makes cancer so lethal. Inthis study, investigators found 78 percent of the DIPG tumors had alterationsin one of two genes that carry instructions for making proteins that playsimilar roles in packaging DNA inside cells. Both belong to the histone H3family of proteins. DNA must be wrapped around histones so that it is compact enoughto fit into the nucleus. The packaging of DNA by histones influences which genesare switched on or off, as well as the repair of mutations in DNA and thestability of DNA. Disruption of any of these processes can contribute tocancer.
Researchers said that the mutations seem unique to aggressivechildhood brain tumors.
“It is amazing to see that this particular tumor typeappears to be characterized by a molecular ‘smoking gun’ and that thesemutations are unique to fast-growing pediatric cancers in the brain,” saysRichard K. Wilson, PhD, director of The Genome Institute at WashingtonUniversity School of Medicine in St. Louis and one of the study’s correspondingauthors. “This is exactly the type of result one hopes to find when studyingthe genomes of cancer patients.”
The results are the latest from the PCGP, an ambitiousthree-year effort to sequence the complete normal and cancer genomes of 600children with some of the most poorly understood and aggressive pediatriccancers. The human genome includes the complete set of instructions needed toassemble and sustain human life. The goal is to identify differences thatexplain why cancer develops, spreads and kills. Researchers believe thefindings will provide the foundation for new tools to diagnose, treat orprevent the disease.
For this study, researchers sequenced the complete normaland cancer genomes of seven patients with DIPG.
“The mutations were found atsuch high frequency in the cancer genomes of those seven patients that weimmediately checked for the same alterations in a larger group of DIPGs,” Bakersays. When researchers sequenced all 16 of the related genes that make closelyrelated variants of histone H3 proteins in an additional 43 DIPGs, they found manyof the tumors contained the same mistakes in only two of these genes.
Of the 50 DIPG tumors included in this study, 60 percent hada single alteration in the makeup of the H3F3Agene. When the mutated gene was translated into a protein, the point mutationled to the substitution of methionine for lysine as the 27th aminoacid in this variant of histone H3 protein. Another 18 percent of the DIPG patientscarried the same mistake in a different gene, HIST1H3B.
Researchers are now working to understand how mutations in H3F3A and HIST1H3B impact cell function and contribute to cancer. Earlierresearch provides some clues. The lysine that is mutated is normally targetedby enzymes that attach other molecules to histone H3, influencing how itinteracts with other proteins that regulate gene expression, Baker says. Mutationsin the enzymes that target histone H3 have been identified in other cancers,but this is the first report showing a specific alteration of histones incancer.
H3F3A and HIST1H3B were also mutated in otheraggressive childhood brain tumors, glioblastoma, that develop outside the brainstem. Of 36 such tumors included in this study, 36 percent carried one of threedistinct point mutations in the genes. The alterations included another singlechange in the makeup of H3F3A notfound in DIPGs.
The histone H3 genes, however, were not mutated in any ofthe 252 other childhood tumors researchers checked for this study. The listincluded the brain tumors known as low-grade gliomas, medulloblastomas andependymomas plus other cancers outside the brain and nervous system. The H3changes have not been reported in any other cancers, including adult glioblastoma.
“This suggests these particular mutations give a very important selectiveadvantage, particularly in the developing brainstem and to a lesser degree inthe developing brain, which leads to a terribly aggressive brain tumor inchildren, but not in adults,” Baker says.
“This discovery would not have been possible without theunbiased approach taken by the Pediatric Cancer Genome Project,” Baker says.“The mutations had not been reported in any other tumor, so we would not havesearched for them in DIPGs. Yet the alterations clearly play an important rolein generating this particular tumor.”
The research was funded in part by the PCGP, including KayJewelers, a lead project sponsor; the National Institutes of Health (NIH), the SydneySchlobohm Chair of Research from the National Brain Tumor Society; the CureStarts Now Foundation, Smile for Sophie Forever Foundation, Tyler’s TreehouseFoundation, Musicians Against Childhood Cancer, the Noyes Brain TumorFoundation and ALSAC.
Washington University School of Medicine
Washington University School of Medicine’s 2,100employed and volunteer faculty physicians also are the medical staff of Barnes-Jewishand St. Louis Children’s hospitals. The School of Medicine is one of theleading medical research, teaching and patient care institutions in the nation,currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations withBarnes-Jewish and St. Louis Children’s hospitals, the School of Medicine islinked to BJC HealthCare.
St. Jude Children’sResearch Hospital
Since opening 50 years ago, St. Jude Children’s ResearchHospital has changed the way the world treats childhood cancer and otherlife-threatening diseases. No family ever pays St. Jude for the care theirchild receives and, for every child treated here, thousands more has been savedworldwide through St. Jude discoveries. The hospital has played a pivotal rolein pushing U.S. pediatric cancer survival rates from 20 to 80 percent overall,and is the first and only National Cancer Institute-designated ComprehensiveCancer Center devoted to children. It is also a leader in the research andtreatment of blood disorders and infectious diseases in children. St. Judewas founded by the late entertainer Danny Thomas, who believed that no childshould die in the dawn of life. Join that mission by visiting www.stjude.org or following us on www.facebook.com/stjude andTwitter @StJudeResearch.