A type of low-grade but sometimes lethal brain tumor in children has been found in many cases to contain an unusual mutation that may help to classify, diagnose and guide the treatment of the tumors, report scientists at Dana-Farber Cancer Institute.
The researchers led a study of pediatric low-grade gliomas, samples of which were collected through an international consortium organized by brain tumor specialists at Dana-Farber/Children's Hospital Cancer Center. Their findings are being published online by the Proceedings of the National Academy of Sciences (PNAS) the week of April 29.
Low-grade gliomas are the most common type of pediatric brain tumors, diagnosed in about 1,000 young patients annually in the United States. There are about 30 distinct types of these tumors, which arise from specialized cells called glia in the brain. Low-grade gliomas are generally slow-growing, said Keith Ligon, MD, PhD, a senior author of the study, but they behave unpredictably and can be life-threatening.
The investigators focused on diffuse low-grade gliomas, so-called because they lack a tumor mass but spread throughout the brain. As a result, diffuse gliomas often recur after surgery and are more likely to evolve into lethal glioblastomas than are non-diffuse low-grade tumors. "Many of these patients do well, but it's hard to generalize as the tumors are difficult to diagnose and study because without better tools pathologists can't name them consistently," explained Ligon, who in addition to being a researcher is also a neuropathologist. The research was undertaken in hopes of identifying a common genetic alteration that could be used to better define and design treatments for them.
The researchers analyzed DNA from 45 tissue samples collected from seven institutions in collaboration with Rameen Beroukhim, MD, PhD, a Dana-Farber genome biologist and co- senior author of the study. They looked for mutations caused by extra or missing copies of DNA code in the tumor genomes.
One alteration stood out: a gene called MYBL1, a transcription factor important for controlling other genes, was rearranged and missing a part of its genetic message in nearly 30 percent of the diffuse tumors categorized as grade 2 in terms of aggressiveness. The scientists went on to show that the mutated version of MYBL1 can cause tumors in mice. Previously MYBL1 was not known to cause cancer, but a closely related gene, MYB, is one of the oldest "proto-oncogenes" -- a normal gene that can become a cancer-causing gene.
"The creation of these truncated genes, reminiscent in structure of the viral oncogene, is a potential driver for this type of tumor," said Lori Ramkissoon, PhD, co-first author along with Peleg Horowitz, MD, PhD, a neurosurgery resident, both of Dana-Farber. "It gives us something to follow up on and investigate the function of this gene. It may lead to a specific test for diagnosing these tumors, and we will also try to determine whether patients who have this mutation do better or worse than those lacking the mutation."
The paper's other authors include investigators and clinicians from Dana-Farber; the Broad Institute; Brigham and Women's Hospital; Boston Children's Hospital; Stanford University School of Medicine; Children's Cancer Hospital, Cairo, Egypt; University of Texas South Western Medical Center, Dallas; Hospital for Sick Children, Toronto; Children's National Medical Center, Washington; Johns Hopkins University School of Medicine; and the University of Calgary.
Research support came from the Pediatric Low Grade Astrocytoma Foundation and other non-profit organizations, as well as the National Institutes of Health (grants P01CA142536, R01CA109467, P30HD018655, U54CA143789, and K08CA122833).
- Lori A. Ramkissoon, Peleg M. Horowitz, Justin M. Craig, Shakti H. Ramkissoon, Benjamin E. Rich, Steven E. Schumacher, Aaron McKenna, Michael S. Lawrence, Guillaume Bergthold, Priscilla K. Brastianos, Barbara Tabak, Matthew D. Ducar, Paul Van Hummelen, Laura E. MacConaill, Tina Pouissant-Young, Yoon-Jae Cho, Hala Taha, Madeha Mahmoud, Daniel C. Bowers, Linda Margraf, Uri Tabori, Cynthia Hawkins, Roger J. Packer, D. Ashley Hill, Scott L. Pomeroy, Charles G. Eberhart, Ian F. Dunn, Liliana Goumnerova, Gad Getz, Jennifer A. Chan, Sandro Santagata, William C. Hahn, Charles D. Stiles, Azra H. Ligon, Mark W. Kieran, Rameen Beroukhim, and Keith L. Ligon. Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. PNAS, April 30, 2013 DOI: 10.1073/pnas.1300252110
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