Among young children, medulloblastoma is among the most common form of brain tumor. Medulloblastoma, which is divided into four subgroups, is partially caused when a mutation occurs in the “driver genes” that either promote or suppress cancerous tumor growth. These mutations can be inherited, sporadic or environmentally induced, but once they appear, they increase the risk for the unfettered and abnormal cell division that leads to malignant tumors. Cancer is quite heterogeneous, but medulloblastoma is specifically very heterogeneous; looking at the driver gene mutation, it’s not as if the majority of medulloblastoma cases have the same mutation. In reality, 5% may have one gene mutation, 3% may have it for another gene and a small percentage may have other mutations. That’s why it cannot be considered as one disease. What’s worse, no specific and effective therapy yet exists for this dangerous disease. Instead, doctors are forced to resort to onerous and invasive treatments like surgery, radiation and chemotherapy, often at the expense of the child’s quality of life.
A team of FSU researchers, led by Professor of Chemistry and Biochemistry Qing-Xiang “Amy” Sang, was interested in learning more about these mutations. Using data from the Catalogue of Somatic Mutations in Cancer, they identified a series of cancer-causing driver gene mutations and discovered that medulloblastoma is perhaps an even more dynamic and variable tumor than expected. Scientists obtained medulloblastoma data from the Catalogue of Somatic Mutations in Cancer (COSMIC), which contains distinct samples that were not previously studied. Using advanced bioinformatics tools, the team was able to pinpoint which driver gene mutations were occurring in which medulloblastoma subgroups. In some cases, they found that mutations once considered specific to one particular subgroup, were causing significant disruption in sister subgroups as well. Medulloblastoma’s heterogeneity makes it an exceptionally difficult cancer to characterize and treat. But with a more nuanced understanding of which mutations happen where and when — and which mutations might defy broadly accepted definitions — researchers will be better equipped to identify opportunities for individualized treatments.
Earlier, in 2014, a French team discovered the intervention of another cancer suppressor for this type of cancer. Researchers first discovered that BCL6, a factor controlling gene expression, controls the conversion of neural stem cells into nerve cells in a part of the brain called cerebellum. The researchers then investigated how BCL6 promotes neurogenesis in the cerebellum. They found that BCL6 acts as an epigenetic “switch” by turning off the gene expression of a major signaling pathway called “Sonic Hedgehog,” (Shh) which normally pushes the neural stem cells to proliferate more and remain undifferentiated. These data provide important information on the mechanisms of brain development, but have also led researchers to examine the role of these mutation in brain cancer. Indeed, the signaling pathway “Sonic Hedgehog had previously been involved in the initiation and growth of a tumor called medulloblastoma (the most common form of brain cancer in children). In this contest the Sonic pathway is a therapeutic target, and Sonic antagonist drugs have already been developed against these tumors, but the tumors quickly develop resistance to these treatments.
Furthermore, this work shows that BCL6 is a natural suppressor of medulloblastomas, whereas earlier work showed that BCL6 is also an oncogene in some blood cancers like leukemia and lymphoma. Thus, the same factor can act as an anti-oncogene in the brain and an oncogene in the blood, illustrating the complexity of the genetics of cancer, which may have other clinical implications. The next step in developing personalized medicines is to develop credible laboratory models of human medulloblastoma tumor subgroups. These brain tumore models, researchers say, will be important evaluative tools in the search for potential therapeutics. The ultimate goal is a regimen of targeted therapies that avoid causing undue burden to vulnerable pediatric patients. Cross-disciplinary collaborations may be a key to finding more effective therapies for this intractable disease. But another crucial key, the team think, will be innovative ideas from a new generation of ambitious researchers. Indeed, this research was led by PhD student scientists.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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