Researchers at the Stanford University School of Medicine and Lucile Packard Children’s Hospital have identified several gene mutations responsible for the most common childhood brain tumor, called medulloblastoma, adding evidence to the theory that the diagnosis is a group of genetically distinct cancers with different prognoses. These and accompanying findings are likely to lead to less toxic, better targeted treatment approaches over the next two years, the researchers said.
“We tend to treat all medulloblastomas as one disease without taking into account how heterogeneous the tumors are at the molecular level,” said Yoon-Jae Cho, MD, an assistant professor of neurology and neurological sciences at Stanford, a pediatric neurologist at Packard Children’s and a co-senior author of the new research. “This paper represents a finer-grained view of the genetic landscape of these tumors and provides us with some leads on how to develop new therapies.” The other senior authors are Scott Pomeroy, MD, PhD, neurologist-in-chief at Children’s Hospital Boston, and Matthew Meyerson, MD, PhD, professor of pathology at Harvard and a senior associate member at the Broad Institute.
Current treatment for medulloblastoma, which originates in the cerebellum and affects about 250 U.S. children each year, begins with surgery to remove as much of the tumor as possible. Patients then receive a combination of radiation and chemotherapy, but the treatments are not tailored to the tumor’s genetic characteristics.
Cho, Pomeroy and Meyerson collaborated to extract DNA from 92 medulloblastoma tumors and compared it with DNA from matched blood samples from the same patients, uncovering 12 significant “point mutations” — single-letter errors in the genetic code — that occurred frequently in the brain cancer. A handful of the mutations had been previously identified in smaller studies of medulloblastoma, but several mutations were novel in both medulloblastoma and in cancer.
Among the newly identified mutations was one in an RNA helicase gene, DDX3X, which Cho said is the second-most common mutation in medulloblastoma tumors. “Mutations in this gene have now also been identified in other tumor types, such as chronic lymphocytic leukemia, and head and neck tumors,” he said.
However, the researchers found that it was rare for the same gene mutated in several different patients’ tumors. More commonly, mutations involving a set of genes regulating a single biological pathway were found in the tumors — a pattern that is emerging across cancer genome sequencing efforts.
Though no single tumor in the study carried all 12 mutations, the researchers were able to categorize the tumors according to which mutations they possessed. “We now understand that there are certain tumors with particular genetic signatures that are really resistant to standard treatments,” Cho said. Children with medulloblastoma do not routinely have their tumors’ genetic signatures characterized, but Cho believes that such characterization coupled with targeted therapies could greatly enhance tumor treatment.
About two-thirds of medulloblastoma patients now survive five years past diagnosis, but many survivors suffer lasting physical or intellectual side effects from their cancer treatments. Drugs tailored to a tumor’s genetic profile have the potential to save more patients while reducing side effects, Cho said.
Several of the mutations discovered affect cellular signals that switch large groups of genes on and off. “The dysregulation of these ‘epigenetic programs’ is becoming a common theme not only in medulloblastoma but across cancer,” Cho said. Such pathways may be good targets for cancer drugs; indeed, drugs targeting one such pathway (histone methyltransferases) are currently in pre-clinical development, while agents against another pathway (Hedgehog signaling pathway) are entering phase-2 clinical trials for medulloblastoma.
Cho is the co-chair of a committee within the Pediatric Brain Tumor Consortium that guides which drugs should be moved into clinical trials next. “Our plan is that within the next one to two years we will be able to offer kids a new set of compounds that have a clear biological rationale based on our genomic studies.” Cho said. “We want to make sure we’re being careful of what we move forward with, but at the same time, for some of these kids we don’t have many, if any, effective and durable treatment options.”
Notes about this brain cancer research article
Cho’s collaborators at Stanford included research associate Furong Yu; Gerald Crabtree, PhD, professor of pathology and of developmental biology and a member of the Stanford Cancer Institute; and life science research assistant Amanda Kautzman.
Written by Erin Digitale Contacts: Erin Digitale – Stanford University Medical Center Robert Dicks – Stanford University Medical Center Source: Stanford University Medical Center press release Image Source: Medulloblastoma image adapted from an image in the public domain from the AFIP Atlas of Tumor Pathology. Feel free to use. Original Research:Abstract for “Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations” by Trevor J. Pugh, Shyamal Dilhan Weeraratne, Tenley C. Archer, Daniel A. Pomeranz Krummel, Daniel Auclair, James Bochicchio, Mauricio O. Carneiro, Scott L. Carter, Kristian Cibulskis, Rachel L. Erlich, Heidi Greulich, Michael S. Lawrence, Niall J. Lennon, Aaron McKenna, James Meldrim, Alex H. Ramos, Michael G. Ross, Carsten Russ, Erica Shefler, Andrey Sivachenko, Brian Sogoloff, Petar Stojanov, Pablo Tamayo, Jill P. Mesirov, Vladimir Amani, Natalia Teider, Soma Sengupta, Jessica Pierre Francois, Paul A. Northcott, Michael D. Taylor, Furong Yu, Gerald R. Crabtree, Amanda G. Kautzman, Stacey B. Gabriel, Gad Getz, Natalie Jäger, David T. W. Jones, Peter Lichter, Stefan M. Pfister, Thomas M. Roberts, Matthew Meyerson, Scott L. Pomeroy and Yoon-Jae Cho in Nature online 22 July 2012 doi: 10.1038/nature11329