Abstract
Brain tumors are the leading cause of cancer-related deaths in children, and medulloblastoma is the most prevalent malignant childhood/pediatric brain tumor. Providing effective treatment for these cancers, with minimal damage to the still-developing brain, remains one of the greatest challenges faced by clinicians. Understanding the diverse events driving tumor formation, maintenance, progression, and recurrence is necessary for identifying novel targeted therapeutics and improving survival of patients with this disease. Genomic copy number alteration data, together with clinical studies, identifies c-MYC amplification as an important risk factor associated with the most aggressive forms of medulloblastoma with marked metastatic potential. Yet despite this, very little is known regarding the impact of such genomic abnormalities upon the functional biology of the tumor cell. We discuss here how recent advances in quantitative proteomic techniques are now providing new insights into the functional biology of these aggressive tumors, as illustrated by the use of proteomics to bridge the gap between the genotype and phenotype in the case of c-MYC-amplified/associated medulloblastoma. These integrated proteogenomic approaches now provide a new platform for understanding cancer biology by providing a functional context to frame genomic abnormalities.
Highlights
Medulloblastoma (MB) is the most common pediatric malignant brain tumor and one of the leading causes of brain cancer deaths in children
All studies to date, including somatic copy number analysis across 1000 medulloblastoma genomes, identify c-MYC copy number amplifications primarily confined to Group 3 tumors [12]
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Summary
Medulloblastoma (MB) is the most common pediatric malignant brain tumor and one of the leading causes of brain cancer deaths in children. Current therapy for high-risk medulloblastoma involves aggressive treatments that often leave survivors with significant neurological and intellectual disabilities due to the effects of these nonspecific cytotoxic therapies on the developing brain [1]. Extensive intertumoral heterogeneity is found in medulloblastoma, with at least four distinct molecular variants identified using genomic profiling techniques [2,3,4]. Significant differences in clinical outcome among these subgroups demonstrate a need for subgroup-specific therapeutic strategies, yet a better understanding of molecular drivers of disease is required before these efforts can be realized [2,5,6]. There is early promise for sonic hedgehog pathway (SHH) inhibitors in a subset of patients with upstream mutations [7,8], there remain few targets for the other subgroups— Group 3 tumors, which have the worst overall survival rates in patients
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