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Starfish infers signatures of complex genomic rearrangements across human cancers

Lisui Bao1,2, Xiaoming Zhong1, Yang Yang1

  • 1Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.

Nature Cancer
|July 14, 2022
PubMed

Insights

Researchers identified new mechanisms driving complex genomic rearrangements (CGRs) in cancer using the Starfish algorithm. This discovery sheds light on cancer genome instability and potential therapeutic targets.

Area of Science:

  • Genomics
  • Cancer Biology
  • Computational Biology

Background:

  • Complex genomic rearrangements (CGRs) are frequent in cancer.
  • CGRs are thought to arise from micronuclei and chromatin bridges, but other mechanisms may exist.

Purpose of the Study:

  • To investigate the mechanisms of CGR formation in cancer.
  • To discover novel CGR signatures and their underlying biological processes.

Main Methods:

  • Development of a computational algorithm, 'Starfish'.
  • Analysis of 2,014 CGRs from 2,428 whole-genome-sequenced (WGS) tumors.
  • Identification of CGR signatures based on copy number and breakpoint patterns.

Main Results:

  • Six distinct CGR signatures were discovered, with high accuracy and biological relevance.
  • Three signatures align with known mechanisms: micronuclei, chromatin bridges, and circular extrachromosomal DNA.
  • Three novel signatures were identified, accounting for over half of the analyzed CGRs.
  • A new mechanism, 'hourglass chromothripsis', characterized by localized breakpoints and minimal DNA loss, was found to be prevalent in prostate cancer and associated with mutant SPOP.

Conclusions:

  • The Starfish algorithm provides a powerful tool for dissecting CGR formation.
  • Novel mechanisms contribute significantly to cancer genome instability.
  • Hourglass chromothripsis represents a distinct CGR mechanism potentially driven by SPOP mutations in prostate cancer.

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