Medulloblastoma, a malignant brain tumor that most commonly affects children, is not one disease but several, said researchers with St. Jude Children’s Hospital in Memphis, Tennessee. Similar discoveries have been made in other cancers, leading to the investigation of new targeted therapies, and Amar Gajjar, MD, cochair of the St. Jude Department of Oncology and a member of the international research team that made the discovery, said he expects the discovery will lead to new, less toxic drugs for children with the wingless (WNT) subtype of medulloblastoma.
Nearly 40% of medulloblastoma tumors are the WNT subtype or the sonic hedgehog (SHH) subtype. Using gene expression mapping, the research team compared expression levels of genes in each tumor type with expression levels of genes found in normal nervous system cells. They suspected that WNT tumors might arise from a grouping of cells in the brain stem. The cells were located below the cerebellum, previously believed to be the area where all medullablastomas originate. Investigators said these cells have never been linked to cancer until now.
To investigate their hypothesis, they conducted in vivo studies using mice. They mutated the CTNNB1 gene, which is specific to the WNT medulloblastoma subtype, in the suspicious group of cells found in the brain stem of the mice. After 6 months, nearly 20% of the mice had medulloblastoma tumors possessing characteristics similar to WNT medullablastomas in humans.
The SHH subtype of medulloblastoma had previously been found to originate in granule neuron precursor cells, which become part of the cerebellum. In this in vivo study, the research team mutated the CTNNB1 gene in these cells and found that it did not affect development in the mouse’s cerebellum or cause medulloblastoma.
In a press release, Richard Gilbertson, MD, PhD, a researcher with the departments of Developmental Neurobiology and Oncology at St. Jude, said, “This study shows clearly that there are distinct subtypes of this cancer that comes from uniquely susceptible cell types in the brain that acquire specific mutations.” Gilbertson is a senior author of the study. He said it appears that the subset of cells where the investigative team believes the WNT subtype of medulloblastoma originates become mossy fiber cells in the adult brainstem, but added that further research is needed to confirm the hypothesis. In addition, the findings seem to indicate that loss of the p53 and TULP4 tumor suppressor genes might spur development of WNT-subtype medulloblastoma.
An earlier team led by Gilbertson discovered that the abnormal activation of certain biochemical pathways indicated whether the tumor would be the WNT subtype, the SHH subtype, or another subtype. They also found that the WNT and SHH subtypes were different microscopically, affected different age groups, and were associated with a different prognosis. Children are more likely to develop SHH-subtype tumors, which are associated with an 80% longterm survival rate. Conversely, WNT-subtype tumors more often affect older adolescents and are almost always curable.
Earlier this year, Gilbertson and associates showed that subtypes of ependymoma, another malignancy that typically occurs in the brain in children and the spine in adults, are also different cancers with different origins. Both studies were published in Nature. “These findings will allow us to better model the heterogeneity we see in the clinic and to move toward designing directed therapies for each tumor subtype,” Gilbertson said.