Englander Institute for Precision Medicine

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

TitleDistinct Classes of Complex Structural Variation Uncovered across Thousands of Cancer Genome Graphs.
Publication TypeJournal Article
Year of Publication2020
AuthorsHadi 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, Wrzeszczynski KO, Arora K, Shah M, Emde A-K, 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 JMiguel, Elemento O, Imielinski M
JournalCell
Volume183
Issue1
Pagination197-210.e32
Date Published2020 Oct 01
ISSN1097-4172
KeywordsChromosome Inversion, Chromothripsis, DNA Copy Number Variations, Gene Rearrangement, Genome, Human, Genomic Structural Variation, Genomics, Humans, Mutation, Neoplasms, Whole Genome Sequencing
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.

DOI10.1016/j.cell.2020.08.006
Alternate JournalCell
PubMed ID33007263
PubMed Central IDPMC7912537
Grant ListUL1 TR000043 / TR / NCATS NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
T32 HG002295 / HG / NHGRI NIH HHS / United States
P01 CA091955 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R35 NS097404 / NS / NINDS NIH HHS / United States
P50 CA247749 / CA / NCI NIH HHS / United States
U24 CA210989 / CA / NCI NIH HHS / United States
P30 CA015704 / CA / NCI NIH HHS / United States
U54 CA193313 / CA / NCI NIH HHS / United States
R01 CA194547 / CA / NCI NIH HHS / United States
F31 CA232465 / CA / NCI NIH HHS / United States
T32 GM132083 / GM / NIGMS NIH HHS / United States

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