@article{d03c0f2ff84f4bfdbb3c0e18efb9b1c5,
title = "Distinct Classes of Complex Structural Variation Uncovered across Thousands of Cancer Genome Graphs",
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, 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",
author = "Kevin Hadi and Xiaotong Yao and Behr, {Julie M.} and Aditya Deshpande and Charalampos Xanthopoulakis and Huasong Tian and Sarah Kudman and Joel Rosiene and Madison Darmofal and Joseph DeRose and Rick Mortensen and Adney, {Emily M.} and Alon Shaiber and Zoran Gajic and Michael Sigouros and Kenneth Eng and Wala, {Jeremiah A.} and Wrzeszczy{\'n}ski, {Kazimierz O.} and Kanika Arora and Minita Shah and Emde, {Anne Katrin} and Vanessa Felice and Frank, {Mayu O.} and Darnell, {Robert B.} and Mahmoud Ghandi and Franklin Huang and Sally Dewhurst and John Maciejowski and {de Lange}, Titia and Jeremy Setton and Nadeem Riaz and Reis-Filho, {Jorge S.} and Simon Powell and Knowles, {David A.} and Ed Reznik and Bud Mishra and Rameen Beroukhim and Zody, {Michael C.} and Nicolas Robine and Oman, {Kenji M.} and Sanchez, {Carissa A.} and Kuhner, {Mary K.} and Smith, {Lucian P.} and Galipeau, {Patricia C.} and Paulson, {Thomas G.} and Reid, {Brian J.} and Xiaohong Li and David Wilkes and Andrea Sboner and Mosquera, {Juan Miguel} and Olivier Elemento and Marcin Imielinski",
note = "Funding Information: M.I. thanks Dan Landau for bio-hermeneutic support; Elli Papaemmanuil for consultation in Eλληνικα; Matthew Meyerson, Scott Carter, and Cheng-Zhong Zhang for discussions early in the development of JaBbA; and Ron Zeira and Tomasz Imielinski for feedback on the JaBbA mathematical formulation. The authors thank Christopher Black and the NYGC ResComp team for high-performance computing support and Bionano genomics for assistance with optical mapping. M.I. X.Y, J.M.B. A.D. J.R. H.T. E.A. and Z.G. were supported by M.I.{\textquoteright}s Burroughs Wellcome Fund Career Award for Medical Scientists, Doris Duke Clinical Foundation Clinical Scientist Development Award, Starr Cancer Consortium Award, National Institutes of Health (NIH) grant U24-CA15020, and Weill Cornell Medicine Department of Pathology and Laboratory Medicine startup funds. M.I. J.M. T.D.L. X.Y. and J.B. were supported by a Melanoma Research Alliance Team Science Award. K.H. was supported by a NIH/NCI F31 graduate research fellowship (F31-CA232465). M.D. was supported by an NIH F32 training grant given to the Tri-Institutional Computational Biology and Medicine PhD Program. R.B. received funding from the Fund for Innovation in Cancer Informatics. B.J.R. T.P. X.L. P.G. C.S. K.O. M.K. and L.S. are supported by NIH funding (P01-CA9195). The IBM-NYGC Cancer Alliance project was supported in part by a grant from the IBM corporation (IBM Watson Health) to the New York Genome Center, New York Genome Center philanthropic funds, and Rockefeller University grant UL1 TR000043 from the National Center for Advancing Translational Sciences (NCATS), and the NIH Clinical and Translational Science Award (CTSA) program. T.G.P. P.C.G. K.M.O. C.A.S. B.J.R. and X.L. were supported by NIH grants P01 CA91955 and P30 CA015704. M.K.K. and L.P.S. were supported by NIH grant P01 CA91955. Bud Mishra was supported by National Science Foundation grants CCF-0836649 and CCF-0926166 and a National Cancer Institute Physical Sciences-Oncology Center grant U54 CA193313-01. Graphical abstract was created with art from BioRender.com under academic license terms. Conceptualization, X.Y. K.H. J.B. J.W. R.B, T.D.L. J.M, J.S. N. Riaz, J.S.R.-F. S.P. and M.I.; Data Curation, X.Y. K.H. J.B, A.D. J.R. M.D, H.T. Z.G. M. Sigouros, K.E. K.O.W. K.A. M. Shah, A.K.E, V.F. M.O.F. M.G. F.H. J.M. N. Robine, K.M.O. C.A.S. M.K.K, L.P.S. P.C.G. T.G.P. X.L. D.W. A.S. J.M.M. and M.I.; Formal Analysis, J.B. K.H. X.Y, A.D. and M.I.; Funding Acquisition, R.D. P.G. B.R. O.E. and M.I.; Investigation, X.Y. J.B. K.H. A.D. and M.I.; Methodology, X.Y. J.B. K.H. A.D. D.K. E.R. B.M. and M.I.; Project Administration, M.I.; Resources, O.E. R.D. M.G. F.H. T.D.L, M.Z. N.R. T.P. P.G. R.S. X.L. B.R. and M.I.; Software, X.Y. J.B. C.X. and M.I.; Supervision, M.I.; Validation, X.Y. J.B. K.H. A.D. and M.I.; Visualization, X.Y. J.B. K.H. C.X. and M.I.; Writing – Original Draft, M.I.; Writing – Review & Editing, all authors. J.S.R.-F. reports receiving personal/consultancy fees from VolitionRx, Paige.AI, Goldman Sachs, REPARE Therapeutics, GRAIL, Ventana Medical Systems, Roche, Genentech, and InviCRO outside of the scope of the submitted work. Funding Information: M.I. thanks Dan Landau for bio-hermeneutic support; Elli Papaemmanuil for consultation in Eλληνικα; Matthew Meyerson, Scott Carter, and Cheng-Zhong Zhang for discussions early in the development of JaBbA; and Ron Zeira and Tomasz Imielinski for feedback on the JaBbA mathematical formulation. The authors thank Christopher Black and the NYGC ResComp team for high-performance computing support and Bionano genomics for assistance with optical mapping. M.I., X.Y, J.M.B., A.D., J.R., H.T., E.A., and Z.G. were supported by M.I.{\textquoteright}s Burroughs Wellcome Fund Career Award for Medical Scientists, Doris Duke Clinical Foundation Clinical Scientist Development Award, Starr Cancer Consortium Award, National Institutes of Health (NIH) grant U24-CA15020 , and Weill Cornell Medicine Department of Pathology and Laboratory Medicine startup funds. M.I., J.M., T.D.L., X.Y., and J.B. were supported by a Melanoma Research Alliance Team Science Award. K.H. was supported by a NIH/NCI F31 graduate research fellowship ( F31-CA232465 ). M.D. was supported by an NIH F32 training grant given to the Tri-Institutional Computational Biology and Medicine PhD Program. R.B. received funding from the Fund for Innovation in Cancer Informatics . B.J.R., T.P., X.L., P.G., C.S., K.O., M.K., and L.S. are supported by NIH funding ( P01-CA9195 ). The IBM-NYGC Cancer Alliance project was supported in part by a grant from the IBM corporation (IBM Watson Health) to the New York Genome Center, New York Genome Center philanthropic funds, and Rockefeller University grant UL1 TR000043 from the National Center for Advancing Translational Sciences (NCATS), and the NIH Clinical and Translational Science Award (CTSA) program. T.G.P., P.C.G., K.M.O., C.A.S., B.J.R., and X.L. were supported by NIH grants P01 CA91955 and P30 CA015704 . M.K.K. and L.P.S. were supported by NIH grant P01 CA91955 . Bud Mishra was supported by National Science Foundation grants CCF-0836649 and CCF-0926166 and a National Cancer Institute Physical Sciences-Oncology Center grant U54 CA193313-01 . Graphical abstract was created with art from BioRender.com under academic license terms. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = oct,
day = "1",
doi = "10.1016/j.cell.2020.08.006",
language = "English (US)",
volume = "183",
pages = "197--210.e32",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "1",
}