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

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

Computer Science

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	197-210.e32
Journal	Cell
Volume	183
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2020.08.006
State	Published - Oct 1 2020

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2020.08.006

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Hadi, K., Yao, X., Behr, J. M., Deshpande, A., Xanthopoulakis, C., Tian, H., Kudman, S., Rosiene, J., Darmofal, M., DeRose, J., Mortensen, R., Adney, E. M., Shaiber, A., Gajic, Z., Sigouros, M., Eng, K., Wala, J. A., Wrzeszczyński, K. O., Arora, K., ... Imielinski, M. (2020). Distinct Classes of Complex Structural Variation Uncovered across Thousands of Cancer Genome Graphs. Cell, 183(1), 197-210.e32. https://doi.org/10.1016/j.cell.2020.08.006

Hadi, K, Yao, X, Behr, JM, Deshpande, A, Xanthopoulakis, C, Tian, H, Kudman, S, Rosiene, J, Darmofal, M, DeRose, J, Mortensen, R, Adney, EM, Shaiber, A, Gajic, Z, Sigouros, M, Eng, K, Wala, JA, Wrzeszczyński, KO, Arora, K, Shah, M, Emde, AK, Felice, V, Frank, MO, Darnell, RB, Ghandi, M, Huang, F, Dewhurst, S, Maciejowski, J, de Lange, T, Setton, J, Riaz, N, Reis-Filho, JS, Powell, S, Knowles, DA, Reznik, E, Mishra, B, Beroukhim, R, Zody, MC, Robine, N, Oman, KM, Sanchez, CA, Kuhner, MK, Smith, LP, Galipeau, PC, Paulson, TG, Reid, BJ, Li, X, Wilkes, D, Sboner, A, Mosquera, JM, Elemento, O & Imielinski, M 2020, 'Distinct Classes of Complex Structural Variation Uncovered across Thousands of Cancer Genome Graphs', Cell, vol. 183, no. 1, pp. 197-210.e32. https://doi.org/10.1016/j.cell.2020.08.006

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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 = "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 = "Elsevier B.V.",

number = "1",

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TY - JOUR

T1 - Distinct Classes of Complex Structural Variation Uncovered across Thousands of Cancer Genome Graphs

AU - Hadi, Kevin

AU - Yao, Xiaotong

AU - Behr, Julie M.

AU - Deshpande, Aditya

AU - Xanthopoulakis, Charalampos

AU - Tian, Huasong

AU - Kudman, Sarah

AU - Rosiene, Joel

AU - Darmofal, Madison

AU - DeRose, Joseph

AU - Mortensen, Rick

AU - Adney, Emily M.

AU - Shaiber, Alon

AU - Gajic, Zoran

AU - Sigouros, Michael

AU - Eng, Kenneth

AU - Wala, Jeremiah A.

AU - Wrzeszczyński, Kazimierz O.

AU - Arora, Kanika

AU - Shah, Minita

AU - Emde, Anne Katrin

AU - Felice, Vanessa

AU - Frank, Mayu O.

AU - Darnell, Robert B.

AU - Ghandi, Mahmoud

AU - Huang, Franklin

AU - Dewhurst, Sally

AU - Maciejowski, John

AU - de Lange, Titia

AU - Setton, Jeremy

AU - Riaz, Nadeem

AU - Reis-Filho, Jorge S.

AU - Powell, Simon

AU - Knowles, David A.

AU - Reznik, Ed

AU - Mishra, Bud

AU - Beroukhim, Rameen

AU - Zody, Michael C.

AU - Robine, Nicolas

AU - Oman, Kenji M.

AU - Sanchez, Carissa A.

AU - Kuhner, Mary K.

AU - Smith, Lucian P.

AU - Galipeau, Patricia C.

AU - Paulson, Thomas G.

AU - Reid, Brian J.

AU - Li, Xiaohong

AU - Wilkes, David

AU - Sboner, Andrea

AU - Mosquera, Juan Miguel

AU - Elemento, Olivier

AU - Imielinski, Marcin

PY - 2020/10/1

Y1 - 2020/10/1

N2 - 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.

AB - 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.

KW - aneuploidy

KW - cancer evolution

KW - cancer genomics

KW - chromothripsis

KW - fragile sites

KW - genome graphs

KW - mutational processes

KW - phasing

KW - structural variation

KW - superenhancers

KW - Mutation/genetics

KW - Humans

KW - Gene Rearrangement/genetics

KW - Genomics/methods

KW - Neoplasms/genetics

KW - Chromothripsis

KW - Genome, Human/genetics

KW - Genomic Structural Variation/genetics

KW - Whole Genome Sequencing/methods

KW - Chromosome Inversion/genetics

KW - DNA Copy Number Variations/genetics

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UR - http://www.scopus.com/inward/citedby.url?scp=85091663377&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2020.08.006

DO - 10.1016/j.cell.2020.08.006

M3 - Article

C2 - 33007263

AN - SCOPUS:85091663377

SN - 0092-8674

VL - 183

SP - 197-210.e32

JO - Cell

JF - Cell

IS - 1

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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