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 Shah; Anne-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

doi:10.1016/j.cell.2020.08.006

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.

Authors

Kevin Hadi¹, Xiaotong Yao², Julie M Behr², Aditya Deshpande², Charalampos Xanthopoulakis³, Huasong Tian¹, Sarah Kudman⁴, Joel Rosiene¹, Madison Darmofal², Joseph DeRose⁵, Rick Mortensen⁵, Emily M Adney¹, Alon Shaiber⁶, Zoran Gajic⁵, Michael Sigouros⁷, Kenneth Eng⁸, Jeremiah A Wala⁹, Kazimierz O Wrzeszczyński⁵, Kanika Arora⁵, Minita Shah⁵, Anne-Katrin Emde⁵, Vanessa Felice⁵, Mayu O Frank¹⁰, Robert B Darnell¹⁰, Mahmoud Ghandi¹¹, Franklin Huang¹², Sally Dewhurst¹³, John Maciejowski¹⁴, Titia de Lange¹³, Jeremy Setton¹⁴, Nadeem Riaz¹⁵, Jorge S Reis-Filho¹⁶, Simon Powell¹⁴, David A Knowles¹⁷, Ed Reznik¹⁸, Bud Mishra¹⁹, Rameen Beroukhim²⁰, Michael C Zody⁵, Nicolas Robine⁵, Kenji M Oman²¹, Carissa A Sanchez²¹, Mary K Kuhner²², Lucian P Smith²³, Patricia C Galipeau²¹, Thomas G Paulson²¹, Brian J Reid²⁴, Xiaohong Li²¹, David Wilkes⁴, Andrea Sboner²⁵, Juan Miguel Mosquera⁴, Olivier Elemento²⁵, Marcin Imielinski²⁶

Affiliations

¹ Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10021, USA; New York Genome Center, New York, NY 10013, USA.
² Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10021, USA; New York Genome Center, New York, NY 10013, USA; Tri-institutional PhD Program in Computational Biology and Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
³ Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
⁴ Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10021, USA; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
⁵ New York Genome Center, New York, NY 10013, USA.
⁶ Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10021, USA; New York Genome Center, New York, NY 10013, USA; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
⁷ Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
⁸ Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10021, USA; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA.
⁹ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Departments of Medical Oncology and Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; School of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁰ New York Genome Center, New York, NY 10013, USA; Laboratory of Molecular Neuro-Oncology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
¹¹ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
¹² Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; School of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
¹³ Laboratory of Cell Biology and Genetics, The Rockefeller University, New York, NY 10065, USA.
¹⁴ Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹⁵ Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹⁶ Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹⁷ New York Genome Center, New York, NY 10013, USA; Department of Computer Science, Columbia University, New York, NY 10027, USA.
¹⁸ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹⁹ Departments of Computer Science, Mathematics and Cell Biology, Courant Institute and NYU School of Medicine, New York University, New York, NY 10012, USA.
²⁰ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Departments of Medical Oncology and Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
²¹ Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
²² Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
²³ Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
²⁴ Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
²⁵ Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10021, USA; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10021, USA; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA.
²⁶ Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10021, USA; New York Genome Center, New York, NY 10013, USA; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10021, USA; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA. Electronic address: mski@mskilab.org.

Abstract

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

Abstract

Publication types

MeSH terms

Grants and funding