Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Isidro Cortés-Ciriano, Jake June-Koo Lee, Ruibin Xi, Dhawal Jain, Youngsook L. Jung, Lixing Yang, Dmitry Gordenin, Leszek J. Klimczak, Cheng-Zhong Zhang, David S. Pellman, PCAWG Structural Variation Working Group, Peter J. Park*, PCAWG Consortium

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

356 Citations (Scopus)
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Abstract

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer.
Original languageEnglish
Pages (from-to)331-341
JournalNature Genetics
Volume52
Issue number3
Early online date5 Feb 2020
DOIs
Publication statusPublished - Mar 2020

Keywords

  • Cancer
  • Computational biology and bioinformatics
  • Genomics

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