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.
Cell. 2020 Oct 1;183(1):197-210.e32. doi: 10.1016/j.cell.2020.08.006.
Kevin Hadi,1,2,21 Xiaotong Yao,1,2,3,21 Julie M. Behr,1,2,3,21 Aditya Deshpande,1,2,3 Charalampos Xanthopoulakis,1 Huasong Tian,1,2 Sarah Kudman,1,4 Joel Rosiene,1,2 Madison Darmofal,1,2,3 Joseph DeRose,2 Rick Mortensen,2 Emily M. Adney,1,2 Alon Shaiber,1,2,4 Zoran Gajic,2 Michael Sigouros,4 Kenneth Eng,4,5 Jeremiah A. Wala,6,7,8 Kazimierz O. Wrzeszczynski,2 Kanika Arora,2 Minita Shah,2 Anne-Katrin Emde,2 Vanessa Felice,2 Mayu O. Frank,2,9 Robert B. Darnell,2,9 Mahmoud Ghandi,6 Franklin Huang,6,8 Sally Dewhurst,10 John Maciejowski,11 Titia de Lange,10 Jeremy Setton,11 Nadeem Riaz,11,12,13 Jorge S. Reis-Filho,12,14 Simon Powell,11 David A. Knowles,2,15 Ed Reznik,16 Bud Mishra,17 Rameen Beroukhim,6,7 Michael C. Zody,2 Nicolas Robine,2 Kenji M. Oman,18 Carissa A. Sanchez,18 Mary K. Kuhner,19 Lucian P. Smith,20 Patricia C. Galipeau,18 Thomas G. Paulson,18 Brian J. Reid,18,19 Xiaohong Li,18 David Wilkes,1,4 Andrea Sboner,1,4,5 Juan Miguel Mosquera,1,4 Olivier Elemento,1,4,5 and Marcin Imielinski1,2,4,5,22,*
1Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10021, USA
2New York Genome Center, New York, NY 10013, USA
3Tri-institutional PhD Program in Computational Biology and Medicine, Weill Cornell Medicine, New York, NY 10021, USA
4Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10021, USA
5Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA
6Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
7Departments of Medical Oncology and Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
8School of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
9Laboratory of Molecular Neuro-Oncology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA 10Laboratory of Cell Biology and Genetics, The Rockefeller University, New York, NY 10065, USA
11Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
12Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
13Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
14Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
15Department of Computer Science, Columbia University, New York, NY 10027, USA
16Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
17Departments of Computer Science, Mathematics and Cell Biology, Courant Institute and NYU School of Medicine, New York University, New York, NY 10012, USA
18Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA 19Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
20Department of Bioengineering, University of Washington, Seattle, WA 98195, USA
21These authors contributed equally
22Lead Contact
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