Genome sequencing of childhood medulloblastoma brain tumors links chromothripsis with TP53 mutations

Genomic rearrangements typically occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving chromosome shattering and reshuffling ('chromothripsis'), for which no genetic basis has yet been described. Whole-genome sequencing of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome) revealed massive, complex rearrangements resulting from chromothripsis. Integrating TP53 status with genomic rearrangement data in additional medulloblastomas revealed a striking association between TP53 mutation and chromothripsis in SHH-MBs. Unexpectedly, five seemingly sporadic SHH-MB patients with chromothripsis harbored TP53 germline mutations – findings relevant for clinical management. Analysis of additional tumor entities substantiated a link between TP53 mutation and chromothripsis, beyond general genomic instability. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings implicate p53 in the initiation of, or cellular reaction to, chromothripsis – a novel role for the 'guardian of the genome'.