Molecular Biology and Genetics of Medulloblastoma

Recent advances in molecular biology have led to the development of powerful tools for the study of medulloblastoma (MB) tumorigenesis, which have revealed new insights into the molecular and genetics basis of this disease. Throughout the life of an individual, the ~3 billion base pairs of DNA that constitute the human genome are exposed to mutagens and suffer errors in DNA replication; this assault leads to the acquisition of stable mutations through rounds of clonal selection and clonal expansion. The cancer genome, as a result of this process, is profoundly different from the genome that composes the constitutional DNA. The goal of cancer genomics is the study of the human cancer genome and the collection and description of all the alterations that make up for its divergence from the constitutional DNA. The mutations, inherited or acquired, contribute in different degrees to the development of cancer and its progression from a localized cancer to one that grows uncontrolled and then metastasizes. Recent studies based on high-throughput mutation detection techniques have shown that cancer genomes harbor from 10 to over 100 mutations. However, these studies are likely to underestimate the alterations caused by genomic rearrangements and copy number alterations (CNA); this suggests that the number of genes hit by somatic mutations is higher. Cell homeostasis can also be disrupted by mechanisms beyond the changes in DNA sequence; changes in DNA methylation status or histone acetylation can alter physiological cell processes like cell division. For this reason a comprehensive description of cancer genetics has to include studies at the level of the genome, epigenome, and transcriptome, as schematized in Fig. 1.