Distinct Classes of Complex Structural Variation Uncovered across Thousands of Cancer Genome Graphs

Cell. 2020 Oct 1;183(1):197-210.e32. doi: 10.1016/j.cell.2020.08.006.


Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be easily classified into simple (e.g., deletion) or complex (e.g., chromothripsis) structural variant classes. Applying a novel genome graph computational paradigm to analyze the topology of junction copy number (JCN) across 2,778 tumor whole-genome sequences, we uncovered three novel complex rearrangement phenomena: pyrgo, rigma, and tyfonas. Pyrgo are "towers" of low-JCN duplications associated with early-replicating regions, superenhancers, and breast or ovarian cancers. Rigma comprise "chasms" of low-JCN deletions enriched in late-replicating fragile sites and gastrointestinal carcinomas. Tyfonas are "typhoons" of high-JCN junctions and fold-back inversions associated with expressed protein-coding fusions, breakend hypermutation, and acral, but not cutaneous, melanomas. Clustering of tumors according to genome graph-derived features identified subgroups associated with DNA repair defects and poor prognosis.

Keywords: aneuploidy; cancer evolution; cancer genomics; chromothripsis; fragile sites; genome graphs; mutational processes; phasing; structural variation; superenhancers.

Publication types

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

MeSH terms

  • Chromosome Inversion / genetics
  • Chromothripsis
  • DNA Copy Number Variations / genetics
  • Gene Rearrangement / genetics
  • Genome, Human / genetics
  • Genomic Structural Variation / genetics*
  • Genomics / methods*
  • Humans
  • Mutation / genetics
  • Neoplasms / genetics*
  • Whole Genome Sequencing / methods