Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations

Cell. 2012 Jan 20;148(1-2):59-71. doi: 10.1016/j.cell.2011.12.013.

Abstract

Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / genetics*
  • Child
  • Chromosome Aberrations
  • DNA Copy Number Variations
  • DNA Mutational Analysis
  • Disease Models, Animal
  • Gene Rearrangement*
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Li-Fraumeni Syndrome / physiopathology
  • Medulloblastoma / genetics*
  • Mice
  • Middle Aged
  • Tumor Suppressor Protein p53 / genetics*

Substances

  • TP53 protein, human
  • Tumor Suppressor Protein p53