Key mutations discovered for most common childhood brain cancer

(Press-News.org) Boston, Mass., July 22, 2012– Researchers at Dana-Farber/Children's Hospital Cancer Center (DF/CHCC) and several collaborating institutions have linked mutations in specific genes to each of the four recognized subtypes of medulloblastoma, the most common malignant brain tumor of children. The discovery, reported July in the journal Nature, provides doctors with potential biomarkers for guiding and individualizing treatment and reveals prospective therapeutic opportunities for countering this devastating malignancy.

The study was conducted by a research team led by Scott Pomeroy, MD, PhD, Neurologist-in-Chief at Boston Children's Hospital and a neuro-oncologist at DF/CHCC; Yoon-Jae Cho, MD, formerly of Boston Children's and now at Stanford University School of Medicine; and Matthew Meyerson, MD, PhD, of Dana-Farber Cancer Institute and the Broad Institute.

Medulloblastomas occur in the cerebellum (the part of the brain that controls balance and other complex motor functions) and are treated with a combination of surgery, radiation and chemotherapy. Though overall survival hovers around 70 percent, most survivors are unable to live independently due to the lasting effects of both tumor and treatment.

Doctors have historically classified medulloblastoma patients as either standard or high risk based on biopsy results, but have long suspected that what we call medulloblastoma could actually be several different diseases. Over the last two years, studies by researchers including Pomeroy and his colleagues have bolstered this view by dividing medulloblastoma into four molecular subtypes based on gene expression profiles and copy number variations. Each subtype has a distinct survival rate, ranging from 20 to 90 percent.

"Not only do we now know how to stratify medulloblastomas genomically, we have a firm grasp of what gene mutations drive each molecular subtype," said Pomeroy, who has spent 20 years trying to understand the biological basis of the tumor's variability. "For the first time, we'll be able to classify and treat medulloblastoma based on molecular typing, providing the best therapy with the fewest long-term consequences."

In this new study, Pomeroy and his team used next generation sequencing technologies to read the full complement of protein-coding genes (also called the exome) of tumors from 92 patients. Within these tumors the team discovered that somatic (that is, non-heritable) mutations occur at very low frequency, one-tenth to one-hundredth of that seen in cancers of adults. Specific gene mutations clustered neatly into the four molecular subtypes, although the majority of genes (88%) were mutated only once in the entire tumor collection. Only 12 genes were mutated in more than one tumor, illustrating medulloblastoma's genetic heterogeneity.

Functionally, the mutated genes fell into two broad categories: genes like Shh and Wnt that play direct roles in molecular pathways controlling cell growth, and genes like DDX3X and GPS2 that play more of a coaching role, modulating the activity of other genes.

Taken as a whole, the study's results confirm the view of medulloblastoma as a family of tumors driven by disruptions in just a few common mechanisms. However, the form those disruptions take—the actual mutations or genomic changes—can vary from tumor to tumor.

"The results reflect two emerging genetic themes seen throughout childhood tumors," Pomeroy noted. "First, very low mutation rates, much lower than those seen in adult tumors, and second, the importance of mutations in genes that regulate the function of the cell's growth pathways but which aren't direct components of those pathways."

Some of the study's findings could be translated to patients relatively quickly. For instance, with the main mutations of each subtype in hand, it should soon be possible to rapidly classify individual medulloblastoma patients' tumors and tailor treatment appropriately based on each subtype's known prognosis. In addition, clinical trials of Shh-blocking drugs already under investigation for other cancers could begin within the next couple of years in patients with the medulloblastoma subtype driven by Shh mutations.

Pomeroy credits the high level of cooperation between groups at different institutions studying medulloblastoma as a significant factor in the progress made over the last few years. "Because of our collective efforts, medulloblastoma has gone from an important but obscure tumor to one that we understand better than many other cancers at the molecular level."

###The study was supported by the National Human Genome Research Institute (grant number U54HG003067), the National Cancer Institute (grant numbers R01CA109467, R01CA105607, R01CA030002, R01CA050661, R01CA154480 and R01CA148699), the National Institute of Neurological Disorders and Stroke (grant numbers R01NS046789 and R25NS070682, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant number P30HD18655) the Canadian Institutes of Health, German Cancer Aid, St. Baldrick's Foundation, the Mullarkey Research Fund, the Pediatric Brain Tumor Foundation and the Howard Hughes Medical Institute.

Boston Children's Hospital is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including nine members of the National Academy of Sciences, 11 members of the Institute of Medicine and nine members of the Howard Hughes Medical Institute comprise Boston Children's research community. Founded as a 20-bed hospital for children, Boston Children's today is a 395 bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Boston Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about research and clinical innovation at Boston Children's, visit: http://vectorblog.org/.

About Dana-Farber/Children's Hospital Cancer Center Dana-Farber/Children's Hospital Cancer Center (DF/CHCC) combines the strengths of Dana-Farber Cancer Institute, a world-class cancer institute, and Boston Children's Hospital, an internationally known pediatric hospital. For over 60 years, these two Harvard Medical School affiliates have provided comprehensive care for children and adolescents with cancer. Committed to conducting research to better understand and treat childhood cancers, DF/CHCC is the Children's Oncology Group's only Phase I Clinical Trial site in New England, is a founding member site of the Pediatric Brain Tumor Consortium and is home to one of the world's most sophisticated and accomplished Pediatric Stem Cell Transplantation centers. DF/CHCC also offers comprehensive transitional and long-term survivorship programs to childhood cancer survivors of all ages.