Medulloblastoma is the most common malignant brain tumor in childhood. It arises in the cerebellum or medulla/brainstem, and shows tremendous biological and clinical heterogeneity. Despite advances in treatment for medulloblastoma over the past few decades, approximately 40% of children who develop this aggressively growing malignancy will experience tumor recurrence, and 30% will die from the disease. Importantly, recent work has shown that medulloblastoma is not a single disease, but comprises at least four distinct molecular subgroups . WNT tumors, displaying activated wingless pathway signaling, carry a favorable prognosis. SHH tumors show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumors are molecularly less well characterized, and present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear.
We have recently described an integrative deep-sequencing analysis of 125 tumor-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project . Here, we focus on genome-wide somatic mutations in medulloblastoma, how they are distributed throughout the genome, how they are correlated with patient age at diagnosis, the influence of subgroup affiliation on mutation rate, and how the mutation allele frequencies can be utilized to predict ploidy and infer temporal evolution of the tumor.