The largest study ever of a rare childhood brain tumor found more than half the tumors carried extra copies of specific genes linked to cancer growth, according to research led by St. Jude Children's Research Hospital investigators.
The findings identify possible new targets for treatment of a tumor in the brainstem known as diffuse intrinsic pontine glioma (DIPG). Current survival rates for children with this cancer are low. Fewer than 10 percent of DIPG patients are alive two years after diagnosis. DIPGs account for 10 to 15 percent of pediatric tumors of the brain and central nervous system.
This study analyzed 43 tumors. Forty-seven percent carried extra copies of genes that transmit signals for cell growth and survival. In 30 percent of tumors, the amplification involved different genes that help control cell division. Twenty-one percent of tumors included genes involved in both mechanisms. The research appears in the September 19 online edition of the Journal of Clinical Oncology.
"Our findings have potential therapeutic relevance and suggest it may be useful to combine drugs that target the pathways disrupted in these tumors both broadly and selectively," said Suzanne Baker, Ph.D., the paper's senior author and member of the St. Jude Department of Developmental Neurobiology.
The work also provided insight into DIPG's origins and added evidence that DIPG is a distinct tumor subtype within a category of brain and spinal tumors known as gliomas. The findings offer the most detailed picture yet of the molecular missteps, including chromosomal changes and altered gene activity, that characterize this tumor.
Efforts to improve patient survival have been hampered in part by limited DIPG samples. "These tumors are one of the most understudied types of cancer because the tumor infiltrates the brainstem, which controls vital functions. It cannot be surgically removed," Baker said. Safety concerns and the accuracy of diagnosis by non-invasive imaging mean that in the U.S. DIPG patients are rarely biopsied.
Baker said these and other research results have prompted renewed discussion about biopsies. "While there may be a rationale for biopsy at diagnosis to determine if specific therapy targets are amplified, our study showed that such amplifications are not always uniformly found within the tumor sample. This suggests that a small biopsy could fail to detect amplification of specific targets, and also that cells within the same tumor may show different responses to selective therapy," she said.
Of the 43 tumors in this study, 37 were donated after autopsy for use in research. Samples of normal tissue were collected as well. Researchers also analyzed other gliomas, including brainstem low-grade gliomas (LGG) and non-brainstem LGG, which occur in the brain outside the brainstem.
Scientists checked for deletions or additions of genetic material at more than 1 million locations across the genome of each tumor. A genome is the complete set of instructions needed to create and sustain a human or other organism. The information is encoded in the DNA molecule, which is packaged into the chromosomes found in nearly every cell.
The screening showed that although DIPGs included extra copies of a variety of genes, two key regulatory mechanisms harbored the most.
Forty-seven percent of DIPGs included extra genes in the receptor tyrosine kinase signaling pathway. This regulatory pathway is disrupted in many tumors and is associated with the unchecked tumor growth and survival that makes cancer deadly. In 30 percent of tumors, the pathway included extra copies of the PDGFRA gene, making it the most commonly amplified gene. Other amplified genes, included MET, IGF1R, ERBB4 and EGFR. In some DIPGs, the pathway included extra copies of more than one of these genes.
Genes that help regulate the cell cycle and cell division were also affected. About 30 percent of DIPGs contained extra copies of the genes that carry instructions for making the Cyclin D family of proteins or the cylin-dependent kinases CDK4 and CDK6.
Chemotherapy agents targeting both pathways are already used to treat other cancers. At St. Jude, a Phase I study is underway using the experimental drug crenolanib to block activity of the PDGFRA protein in DIPGs and related tumors.
When researchers compared gene activity in 27 DIPGs with results from other gliomas found outside the brainstem in both children and adults, they identified significant differences. Baker said those differences offer clues about where DIPGs begin and suggest the HOX family of genes might be involved. "We saw much higher expression of particular HOX gene family members in DIPGs compared to non-brainstem gliomas," she said. This gene family plays an important developmental role in a range of organisms.
The study's first authors are Barbara Paugh, Ph.D., a postdoctoral fellow in Baker's laboratory, and Alberto Broniscer, M.D., associate member of the St. Jude Department of Oncology. Other authors are Chunxu Qu, Claudia Miller, Junyuan Zhang, Ruth Tatevossian, Arzu Onar-Thomas, Justin Baker, Amar Gajjar and David Ellison, all of St. Jude; James Olson and J. Russell Geyer, both of the University of Washington, Seattle; Susan Chi, Dana Farber Cancer Institute, Boston; and Nasjla Saba da Silva, Universidade Federal de Sao Paulo, Brazil.
The research was supported in part by the National Institutes of Health, the National Brain Tumor Society, The Cure Starts Now Foundation, the Smile for Sophie Forever Foundation, Tyler's Treehouse Foundation, Musicians Against Childhood Cancer, the Noyes Brain Tumor Foundation, the Pediatric Low Grade Astrocytoma Foundation and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering research and treatment of children with cancer and other life-threatening diseases. The hospital's research has helped push overall survival rates for childhood cancer from less than 20 percent when the institution opened to almost 80 percent today. It is the first and only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children, and no family ever pays St. Jude for care. For more information, visit www.stjude.org.
Carrie Strehlau | EurekAlert!
Study relating to materials testing Detecting damages in non-magnetic steel through magnetism
23.07.2018 | Technische Universität Kaiserslautern
Innovative genetic tests for children with developmental disorders and epilepsy
11.07.2018 | Christian-Albrechts-Universität zu Kiel
Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.
When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...
Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.
Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....
Proteins must be folded correctly to fulfill their molecular functions in cells. Molecular assistants called chaperones help proteins exploit their inbuilt folding potential and reach the correct three-dimensional structure. Researchers at the Max Planck Institute of Biochemistry (MPIB) have demonstrated that actin, the most abundant protein in higher developed cells, does not have the inbuilt potential to fold and instead requires special assistance to fold into its active state. The chaperone TRiC uses a previously undescribed mechanism to perform actin folding. The study was recently published in the journal Cell.
Actin is the most abundant protein in highly developed cells and has diverse functions in processes like cell stabilization, cell division and muscle...
Scientists have discovered that the electrical resistance of a copper-oxide compound depends on the magnetic field in a very unusual way -- a finding that could help direct the search for materials that can perfectly conduct electricity at room temperatur
What happens when really powerful magnets--capable of producing magnetic fields nearly two million times stronger than Earth's--are applied to materials that...
The quality of materials often depends on the manufacturing process. In casting and welding, for example, the rate at which melts solidify and the resulting microstructure of the alloy is important. With metallic foams as well, it depends on exactly how the foaming process takes place. To understand these processes fully requires fast sensing capability. The fastest 3D tomographic images to date have now been achieved at the BESSY II X-ray source operated by the Helmholtz-Zentrum Berlin.
Dr. Francisco Garcia-Moreno and his team have designed a turntable that rotates ultra-stably about its axis at a constant rotational speed. This really depends...
08.08.2018 | Event News
27.07.2018 | Event News
25.07.2018 | Event News
14.08.2018 | Information Technology
14.08.2018 | Life Sciences
14.08.2018 | Life Sciences