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Patterns of somatic structural variation in human cancer genomes

Author

Listed:
  • Yilong Li

    (Wellcome Trust Sanger Institute
    Totient Inc)

  • Nicola D. Roberts

    (Wellcome Trust Sanger Institute)

  • Jeremiah A. Wala

    (The Broad Institute of Harvard and MIT
    Harvard University
    Dana-Farber Cancer Institute)

  • Ofer Shapira

    (The Broad Institute of Harvard and MIT
    Harvard University
    Dana-Farber Cancer Institute)

  • Steven E. Schumacher

    (The Broad Institute of Harvard and MIT
    Harvard University
    Dana-Farber Cancer Institute)

  • Kiran Kumar

    (The Broad Institute of Harvard and MIT
    Harvard University
    Dana-Farber Cancer Institute)

  • Ekta Khurana

    (Weill Cornell Medical College)

  • Sebastian Waszak

    (Genome Biology Unit)

  • Jan O. Korbel

    (Genome Biology Unit)

  • James E. Haber

    (Brandeis University)

  • Marcin Imielinski

    (New York Genome Center)

  • Joachim Weischenfeldt

    (University of Copenhagen)

  • Rameen Beroukhim

    (The Broad Institute of Harvard and MIT
    Harvard University
    Dana-Farber Cancer Institute)

  • Peter J. Campbell

    (Wellcome Trust Sanger Institute
    University of Cambridge)

Abstract

A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes1–7. Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types8. Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions—as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2–7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and—in liver cancer—frequently activate the telomerase gene TERT. A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.

Suggested Citation

  • Yilong Li & Nicola D. Roberts & Jeremiah A. Wala & Ofer Shapira & Steven E. Schumacher & Kiran Kumar & Ekta Khurana & Sebastian Waszak & Jan O. Korbel & James E. Haber & Marcin Imielinski & Joachim We, 2020. "Patterns of somatic structural variation in human cancer genomes," Nature, Nature, vol. 578(7793), pages 112-121, February.
  • Handle: RePEc:nat:nature:v:578:y:2020:i:7793:d:10.1038_s41586-019-1913-9
    DOI: 10.1038/s41586-019-1913-9
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