Genome Sequencing of Pediatric Medulloblastoma Links Catastrophic DNA Rearrangements with TP53 Mutations

By Tobias Rausch, David T. W. Jones, M. Zapatka, A. Stütz, T. Zichner, J. Weischenfeldt, N. Jäger, M. Remke, D. Shih, P. Northcott and 41 more. Cell, 2012

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SUMMARY 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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2f685aa1afbf818470c11c953ab30af6bd82e862

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Citations in the corpus

Patterns of somatic structural variation in human cancer genomes (2020, neutral): “7−−24kb C (66) 10−−98kb D (22) 23−−640kb E (71) 40−−280kb F (75) 120−−540kb G (8) 250−−2000kb 1k b 1M b 1k b 1M b 1k b 1M b 1k b 1M b 1k b 1M b 1k b 1M b 1k b 1M b”
Chromothripsis and kataegis induced by telomere crisis (2015, neutral): “Chromothripsis has been observed across many tumor types (Forment et al., 2012), especially those with p53 loss (Rausch et al., 2012), aswell as occasional occurrence in the germline (Kloosterman and Cuppen, 2013).”
DELLY: structural variant discovery by integrated paired-end and split-read analysis (2012, methodology): “…datasets at single-nucleotide resolution, as an optimal basis for investigating the formation mechanisms and functional consequences of SVs. Results: We have developed an SV discovery method, called DELLY, that integrates short insert paired-ends, long-range matepairs and split-read alignments to…”
Lessons from the cancer genome. (2013, neutral): “Interestingly, these replication-dependent rearrangements show a strong correlation with TP53 mutations in subtypes of medulloblastoma (Rausch et al., 2012).”
Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. (2015, background): “It is plausible that CDKN2A has a role in chromothripsis, as it affects the TP53 pathway, which has been shown to be involved in chromothripsis in other entities (Rausch et al., 2012), but we found no direct correlation between chromothripsis and focal CDKN2A deletions.”
Melanoma genome sequencing reveals frequent PREX2 mutations (2012, neutral): “This pattern is reminiscent of chromothripsis 14 , a process involving catastrophic chromosome breakage that has been observed in several tumor types 15,16 .”
Punctuated Evolution of Prostate Cancer Genomes (2013, neutral): “On the opposite end of the spectrum, extreme instances of chromothripsis can induce massive (albeit relatively localized) DNA damage at once, often with oncogenic consequences (Rausch et al., 2012; Stephens et al., 2011).”