Editors' ChoiceMedulloblastoma

The Mutation That Broke the Cell’s Back

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Science Translational Medicine  15 Feb 2012:
Vol. 4, Issue 121, pp. 121ec25
DOI: 10.1126/scitranslmed.3003837

The tumor suppressor gene p53 is often referred to as the guardian of the genome. Its role in ensuring the integrity of the genome is thought to be critical in preventing the development of tumors, in part by blocking progressive genomic rearrangements. However, recent findings suggest that an alternative mechanism, chromothripsis—a one-step catastrophic event that involves numerous simultaneous genomic rearrangements—can occur in ~2 to 3% of cancers, particularly in pediatric malignancies. Rausch et al. have shown that indeed this event is the likely cause of a subset of pediatric medulloblastomas—Sonic-Hedgehog subtype medulloblastoma (SHH-MB)—in patients with Li-Fraumeni syndrome, an autosomal dominant hereditary disorder that is associated with germline mutations of TP53.

In a series of elegant experiments, Rausch et al. performed whole-genome sequencing of samples of SHH-MB in Li-Fraumeni patients and found highly complex DNA rearrangements (chromothripsis). DNA copy analysis in a larger set of samples revealed that only those medulloblastoma samples with TP53 mutations had chromothripsis. Moreover, chromothripsis was present in SHH-MB mouse models lacking the p53 ortholog (Trp53), but those SHH-MB models with functional Trp53 showed no chromothripsis. The investigators then extended this association to Li-Fraumeni patients with acute myeloid leukemia. Thus, germline TP53 mutations appear to be a critical event leading to the catastrophic genomic reorganization that results in these devastating pediatric malignancies. Although the importance of the p53 tumor suppressor gene to tumor development is clear, a key challenge remains—how to prevent or reverse the effects of mutated p53 for which no current therapy exists.

T. Rausch et al., Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 148, 59–71 (2012). [Abstract]

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