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

Kevin Hadi, Xiaotong Yao, Julie M. Behr, Aditya Deshpande, Charalampos Xanthopoulakis, Huasong Tian, Sarah Kudman, Joel Rosiene, Madison Darmofal, Joseph DeRose, Rick Mortensen, Emily M. Adney, Alon Shaiber, Zoran Gajic, Michael Sigouros, Kenneth Eng, Jeremiah A. Wala, Kazimierz O. Wrzeszczyński, Kanika Arora, Minita ShahAnne Katrin Emde, Vanessa Felice, Mayu O. Frank, Robert B. Darnell, Mahmoud Ghandi, Franklin Huang, Sally Dewhurst, John Maciejowski, Titia de Lange, Jeremy Setton, Nadeem Riaz, Jorge S. Reis-Filho, Simon Powell, David A. Knowles, Ed Reznik, Bud Mishra, Rameen Beroukhim, Michael C. Zody, Nicolas Robine, Kenji M. Oman, Carissa A. Sanchez, Mary K. Kuhner, Lucian P. Smith, Patricia C. Galipeau, Thomas G. Paulson, Brian J. Reid, Xiaohong Li, David Wilkes, Andrea Sboner, Juan Miguel Mosquera, Olivier Elemento, Marcin Imielinski

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)197-210.e32
Issue number1
StatePublished - Oct 1 2020


  • aneuploidy
  • cancer evolution
  • cancer genomics
  • chromothripsis
  • fragile sites
  • genome graphs
  • mutational processes
  • phasing
  • structural variation
  • superenhancers
  • Mutation/genetics
  • Humans
  • Gene Rearrangement/genetics
  • Genomics/methods
  • Neoplasms/genetics
  • Chromothripsis
  • Genome, Human/genetics
  • Genomic Structural Variation/genetics
  • Whole Genome Sequencing/methods
  • Chromosome Inversion/genetics
  • DNA Copy Number Variations/genetics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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