Abstract
Structural variations (SVs) affect more of the cancer genome than any other type of somatic genetic alteration but difficulties in detecting and interpreting them have limited our understanding. Clinical cancer sequencing also increasingly aims to detect SVs, leading to a widespread necessity to interpret their biological and clinical relevance. Recently, analyses of large whole-genome sequencing data sets revealed features that impact rates of SVs across the genome in different cancers. A striking feature has been the extent to which, in both their generation and their influence on the selective fitness of cancer cells, SVs are more specific to individual cancer types than other genetic alterations such as single-nucleotide variants. This Perspective discusses how the folding of the 3D genome, and differences in its folding across cell types, affect observed SV rates in different cancer types as well as how SVs can impact cancer cell fitness.
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References
Tallman, M. S. et al. All-trans-retinoic acid in acute promyelocytic leukemia. N. Engl. J. Med. 337, 1021–1028 (1997).
Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).
Druker, B. J. et al. Efficacy and safety of a specific inhibitor of the BCR–ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344, 1031–1037 (2001).
Wala, J. A. et al. SvABA: genome-wide detection of structural variants and indels by local assembly. Genome Res. 28, 581–591 (2018).
Rheinbay, E. et al. Analyses of non-coding somatic drivers in 2,658 cancer whole genomes. Nature 578, 102–111 (2020).
Gong, T., Hayes, V. M. & Chan, E. K. F. Detection of somatic structural variants from short-read next-generation sequencing data. Brief. Bioinform 22, bbaa056 (2021).
Weischenfeldt, J. et al. Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking. Nat. Genet. 49, 65–74 (2016).
Bandopadhayay, P. et al. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat. Genet. 48, 273–282 (2016).
Northcott, P. A. et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511, 428–434 (2014).
Newman, S. et al. Genomes for kids: the scope of pathogenic mutations in pediatric cancer revealed by comprehensive DNA and RNA sequencing. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-20-1631 (2021).
Staaf, J. et al. Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study. Nat. Med. 25, 1526–1533 (2019).
Duncavage, E. J. et al. Genome sequencing as an alternative to cytogenetic analysis in myeloid cancers. N. Engl. J. Med. 384, 924–935 (2021).
Zack, T. I. et al. Pan-cancer patterns of somatic copy number alteration. Nat. Genet. 45, 1134–1140 (2013).
Cho, S. W. et al. Promoter of lncRNA gene PVT1 is a tumor-suppressor DNA boundary element. Cell 173, 1398–1412.e22 (2018).
Morton, A. R. et al. Functional enhancers shape extrachromosomal oncogene amplifications. Cell 179, 1330–1341.e13 (2019).
Chiang, C. et al. The impact of structural variation on human gene expression. Nat. Genet. 49, 692–699 (2017).
Audano, P. A. et al. Characterizing the major structural variant alleles of the human genome. Cell 176, 663–675.e19 (2019).
Merker, J. D. et al. Long-read genome sequencing identifies causal structural variation in a Mendelian disease. Genet. Med. 20, 159–163 (2018).
Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007).
Li, Y. et al. Patterns of somatic structural variation in human cancer genomes. Nature 578, 112–121 (2020).
ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature 578, 82–93 (2020).
Spielmann, M., Lupiáñez, D. G. & Mundlos, S. Structural variation in the 3D genome. Nat. Rev. Genet. 19, 453–467 (2018).
Fudenberg, G., Getz, G., Meyerson, M. & Mirny, L. A. High order chromatin architecture shapes the landscape of chromosomal alterations in cancer. Nat. Biotechnol. 29, 1109–1113 (2011).
Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009).
Kim, H. et al. Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers. Nat. Genet. 52, 891–897 (2020).
Turner, K. M. et al. Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity. Nature 543, 122–125 (2017).
Wu, S. et al. Circular ecDNA promotes accessible chromatin and high oncogene expression. Nature 575, 699–703 (2019).
Scheble, V. J. et al. ERG rearrangement is specific to prostate cancer and does not occur in any other common tumor. Mod. Pathol. 23, 1061–1067 (2010).
Zheng, H. & Xie, W. The role of 3D genome organization in development and cell differentiation. Nat. Rev. Mol. Cell Biol. 20, 535–550 (2019).
Bintu, B. et al. Super-resolution chromatin tracing reveals domains and cooperative interactions in single cells. Science 362, eaau1783 (2018).
Mirny, L. A. The fractal globule as a model of chromatin architecture in the cell. Chromosome Res. 19, 37–51 (2011).
Meaburn, K. J. & Misteli, T. Cell biology: chromosome territories. Nature 445, 379–781 (2007).
Rao, S. S. et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159, 1665–1680 (2014).
Boyle, S. et al. The spatial organization of human chromosomes within the nuclei of normal and emerin-mutant cells. Hum. Mol. Genet. 10, 211–219 (2001).
Szabo, Q., Bantignies, F. & Cavalli, G. Principles of genome folding into topologically associating domains. Sci. Adv. 5, eaaw1668 (2019).
Strom, A. R. et al. Phase separation drives heterochromatin domain formation. Nature 547, 241–245 (2017).
de Wit, E. et al. CTCF binding polarity determines chromatin looping. Mol. Cell 60, 676–684 (2015).
Symmons, O. et al. Functional and topological characteristics of mammalian regulatory domains. Genome Res. 24, 390–400 (2014).
Mifsud, B. et al. Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C. Nat. Genet. 47, 598–606 (2015).
Dixon, J. R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380 (2012).
Bell, A. C., West, A. G. & Felsenfeld, G. The protein CTCF is required for the enhancer blocking activity of vertebrate insulators. Cell 98, 387–396 (1999).
Parelho, V. et al. Cohesins functionally associate with CTCF on mammalian chromosome arms. Cell 132, 422–433 (2008).
Sanborn, A. L. et al. Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes. Proc. Natl Acad. Sci. USA 112, E6456–E6465 (2015).
Ernst, J. & Kellis, M. ChromHMM: automating chromatin-state discovery and characterization. Nat. Methods 9, 215–216 (2012).
Dekker, J., Marti-Renom, M. A. & Mirny, L. A. Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data. Nat. Rev. Genet. 14, 390–403 (2013).
Fortin, J.-P. & Hansen, K. D. Reconstructing A/B compartments as revealed by Hi-C using long-range correlations in epigenetic data. Genome Biol. 16, 180 (2015).
Finn, E. H. et al. Extensive heterogeneity and intrinsic variation in spatial genome organization. Cell 176, 1502–1515.e10 (2019).
Cattoni, D. I. et al. Single-cell absolute contact probability detection reveals chromosomes are organized by multiple low-frequency yet specific interactions. Nat. Commun. 8, 1753 (2017).
Aitken, S. J. et al. CTCF maintains regulatory homeostasis of cancer pathways. Genome Biol. 19, 106 (2018).
Hyle, J. et al. Acute depletion of CTCF directly affects MYC regulation through loss of enhancer–promoter looping. Nucleic Acids Res. 47, 6699–6713 (2019).
Sima, J. et al. Identifying cis elements for spatiotemporal control of mammalian DNA replication. Cell 176, 816–830.e18 (2019).
Feng, Y. & Pauklin, S. Revisiting 3D chromatin architecture in cancer development and progression. Nucleic Acids Res. 48, 10632–10647 (2020).
Fritz, A. J. et al. Wide-scale alterations in interchromosomal organization in breast cancer cells: defining a network of interacting chromosomes. Hum. Mol. Genet. 23, 5133–5146 (2014).
Hnisz, D., Schuijers, J., Li, C. H. & Young, R. A. Regulation and dysregulation of chromosome structure in cancer. Annu. Rev. Cancer Biol. 2, 21–40 (2018).
van Steensel, B. & Belmont, A. S. Lamina-associated domains: links with chromosome architecture, heterochromatin, and gene repression. Cell 169, 780–791 (2017).
Zhang, C.-Z. et al. Chromothripsis from DNA damage in micronuclei. Nature 522, 179–184 (2015).
Umbreit, N. T. et al. Mechanisms generating cancer genome complexity from a single cell division error. Science 368, eaba0712 (2020).
Lemaître, C. et al. Nuclear position dictates DNA repair pathway choice. Genes Dev. 28, 2450–2463 (2014).
Stratton, M. R., Campbell, P. J. & Futreal, P. A. The cancer genome. Nature 458, 719–724 (2009).
Martincorena, I. et al. Universal patterns of selection in cancer and somatic tissues. Cell 173, 1823 (2018).
Lawrence, M. S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).
Zhang, C.-Z. & Pellman, D. Cancer genomic rearrangements and copy number alterations from errors in cell division. Annu. Rev.Cancer Biol. https://doi.org/10.1146/annurev-cancerbio-070620-094029 (2022).
Liu, P. et al. Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell 146, 889–903 (2011).
Zhang, C.-Z. & Pellman, D. From mutational mechanisms in single cells to mutational patterns in cancer genomes. Cold Spring Harb. Symp. Quant. Biol. 80, 117–137 (2015).
Anand, R. P., Lovett, S. T. & Haber, J. E. Break-induced DNA replication. Cold Spring Harb. Perspect. Biol. 5, a010397 (2013).
Hungerford, D. A. A minute chromosome in human chronic granulocytic leukemia. Science 132, 1497–1499 (1960).
Neves, H., Ramos, C., da Silva, M. G., Parreira, A. & Parreira, L. The nuclear topography of ABL, BCR, PML, and RARα genes: evidence for gene proximity in specific phases of the cell cycle and stages of hematopoietic differentiation. Blood 93, 1197–1207 (1999).
Lukásová, E. et al. Localisation and distance between ABL and BCR genes in interphase nuclei of bone marrow cells of control donors and patients with chronic myeloid leukaemia. Hum. Genet. 100, 525–535 (1997).
Roix, J. J., McQueen, P. G., Munson, P. J., Parada, L. A. & Misteli, T. Spatial proximity of translocation-prone gene loci in human lymphomas. Nat. Genet. 34, 287–291 (2003).
Klein, I. A. et al. Translocation-capture sequencing reveals the extent and nature of chromosomal rearrangements in B lymphocytes. Cell 147, 95–106 (2011).
Gerhauser, C. et al. Molecular evolution of early-onset prostate cancer identifies molecular risk markers and clinical trajectories. Cancer Cell 34, 996–1011.e8 (2018).
Haffner, M. C., De Marzo, A. M., Meeker, A. K., Nelson, W. G. & Yegnasubramanian, S. Transcription-induced DNA double strand breaks: both oncogenic force and potential therapeutic target? Clin. Cancer Res. 17, 3858–3864 (2011).
Canela, A. et al. Genome organization drives chromosome fragility. Cell 170, 507–521.e18 (2017).
Polak, P. et al. Cell-of-origin chromatin organization shapes the mutational landscape of cancer. Nature 518, 360–364 (2015).
Yang, L. et al. Diverse mechanisms of somatic structural variations in human cancer genomes. Cell 153, 919–929 (2013).
Aymard, F. et al. Genome-wide mapping of long-range contacts unveils clustering of DNA double-strand breaks at damaged active genes. Nat. Struct. Mol. Biol. 24, 353–361 (2017).
Pfister, S. X. et al. SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability. Cell Rep. 7, 2006–2018 (2014).
Kilic, S. et al. Phase separation of 53BP1 determines liquid-like behavior of DNA repair compartments. EMBO J. 38, e101379 (2019).
Ochs, F. et al. Stabilization of chromatin topology safeguards genome integrity. Nature 574, 571–574 (2019).
Baca, S. C. et al. Punctuated evolution of prostate cancer genomes. Cell 153, 666–677 (2013).
Sakofsky, C. J. et al. Translesion polymerases drive microhomology-mediated break-induced replication leading to complex chromosomal rearrangements. Mol. Cell 60, 860–872 (2015).
Zhang, F. et al. The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans. Nat. Genet. 41, 849–853 (2009).
Sidiropoulos, N. et al. Somatic structural variant formation is guided by and influences genome architecture. Genome Res. 32, 643–655 (2022).
Ryba, T. et al. Evolutionarily conserved replication timing profiles predict long-range chromatin interactions and distinguish closely related cell types. Genome Res. 20, 761–770 (2010).
Parada, L. A., McQueen, P. G., Munson, P. J. & Misteli, T. Conservation of relative chromosome positioning in normal and cancer cells. Curr. Biol. 12, 1692–1697 (2002).
Marshall, W. F. et al. Interphase chromosomes undergo constrained diffusional motion in living cells. Curr. Biol. 7, 930–939 (1997).
Miné-Hattab, J. & Rothstein, R. Increased chromosome mobility facilitates homology search during recombination. Nat. Cell Biol. 14, 510–517 (2012).
Polo, S. E. & Jackson, S. P. Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes Dev. 25, 409–433 (2011).
Juhász, S. et al. The chromatin remodeler ALC1 underlies resistance to PARP inhibitor treatment. Sci. Adv. 6, eabb8626 (2020).
Clouaire, T. et al. Comprehensive mapping of histone modifications at DNA double-strand breaks deciphers repair pathway chromatin signatures. Mol. Cell 72, 250–262.e6 (2018).
Lottersberger, F., Karssemeijer, R. A., Dimitrova, N. & de Lange, T. 53BP1 and the LINC complex promote microtubule-dependent DSB mobility and DNA repair. Cell 163, 880–893 (2015).
Ribeiro de Almeida, C. et al. The DNA-binding protein CTCF limits proximal Vκ recombination and restricts κ enhancer interactions to the immunoglobulin κ light chain locus. Immunity 35, 501–513 (2011).
Guo, C. et al. CTCF-binding elements mediate control of V(D)J recombination. Nature 477, 424–430 (2011).
Fungtammasan, A., Walsh, E., Chiaromonte, F., Eckert, K. A. & Makova, K. D. A genome-wide analysis of common fragile sites: what features determine chromosomal instability in the human genome? Genome Res. 22, 993–1005 (2012).
Bianco, S. et al. Polymer physics predicts the effects of structural variants on chromatin architecture. Nat. Genet. 50, 662–667 (2018).
Engreitz, J. M., Agarwala, V. & Mirny, L. A. Three-dimensional genome architecture influences partner selection for chromosomal translocations in human disease. PLoS ONE 7, e44196 (2012).
De, S. & Michor, F. DNA secondary structures and epigenetic determinants of cancer genome evolution. Genome Biol. 11, P10 (2010).
Nora, E. P. et al. Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization. Cell 169, 930–944.e22 (2017).
Fudenberg, G., Kelley, D. R. & Pollard, K. S. Predicting 3D genome folding from DNA sequence with Akita. Nat. Methods https://doi.org/10.1038/s41592-020-0958-x (2020).
Glover, T. W., Wilson, T. E. & Arlt, M. F. Fragile sites in cancer: more than meets the eye. Nat. Rev. Cancer 17, 489–501 (2017).
Sarni, D. et al. 3D genome organization contributes to genome instability at fragile sites. Nat. Commun. 11, 3613 (2020).
Haffner, M. C. et al. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat. Genet. 42, 668–675 (2010).
Lin, C. et al. Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer. Cell 139, 1069–1083 (2009).
Zhang, C.-Z., Leibowitz, M. L. & Pellman, D. Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements. Genes Dev. 27, 2513–2530 (2013).
Davis, A., Gao, R. & Navin, N. Tumor evolution: linear, branching, neutral or punctuated? Biochim. Biophys. Acta Rev. Cancer 1867, 151–161 (2017).
Heng, H. H. Q. et al. The evolutionary mechanism of cancer. J. Cell. Biochem. 109, 1072–1084 (2010).
Cortés-Ciriano, I. et al. Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing. Nat. Genet. 52, 331–341 (2020).
Stephens, P. J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011).
Nichols, C. A. et al. Loss of heterozygosity of essential genes represents a widespread class of potential cancer vulnerabilities. Nat. Commun. 11, 2517 (2020).
Williams, M. J. et al. Quantification of subclonal selection in cancer from bulk sequencing data. Nat. Genet. 50, 895–903 (2018).
Davoli, T. et al. Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns and shape the cancer genome. Cell 155, 948–962 (2013).
Solimini, N. L. et al. Recurrent hemizygous deletions in cancers may optimize proliferative potential. Science https://doi.org/10.1126/science.1219580 (2012).
Lhoumaud, P. et al. NSD2 overexpression drives clustered chromatin and transcriptional changes in a subset of insulated domains. Nat. Commun. 10, 4843 (2019).
Lupiáñez, D. G. et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene–enhancer interactions. Cell 161, 1012–1025 (2015).
Akdemir, K. C. et al. Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer. Nat. Genet. 52, 294–305 (2020).
Rao, S. S. P. et al. Cohesin loss eliminates all loop domains. Cell 171, 305–320.e24 (2017).
Bonev, B. et al. Multiscale 3D genome rewiring during mouse neural development. Cell 171, 557–572.e24 (2017).
Spitz, F. & Furlong, E. E. M. Transcription factors: from enhancer binding to developmental control. Nat. Rev. Genet. 13, 613–626 (2012).
Gasperini, M., Tome, J. M. & Shendure, J. Towards a comprehensive catalogue of validated and target-linked human enhancers. Nat. Rev. Genet. 21, 292–310 (2020).
Andersson, R. & Sandelin, A. Determinants of enhancer and promoter activities of regulatory elements. Nat. Rev. Genet. 21, 71–87 (2020).
Despang, A. et al. Functional dissection of the Sox9–Kcnj2 locus identifies nonessential and instructive roles of TAD architecture. Nat. Genet. 51, 1263–1271 (2019).
Villar, D. et al. Enhancer evolution across 20 mammalian species. Cell 160, 554–566 (2015).
Bahr, C. et al. A Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies. Nature 553, 515–520 (2018).
Northcott, P. A. et al. The whole-genome landscape of medulloblastoma subtypes. Nature 547, 311–317 (2017).
Sin-Chan, P. et al. A C19MC–LIN28A–MYCN oncogenic circuit driven by hijacked super-enhancers is a distinct therapeutic vulnerability in ETMRs: a lethal brain tumor. Cancer Cell 36, 51–67.e7 (2019).
Northcott, P. A., Pfister, S. M. & Jones, D. T. Next-generation (epi)genetic drivers of childhood brain tumours and the outlook for targeted therapies. Lancet Oncol. 16, e293–e302 (2015).
Schilling, G. et al. Molecular characterization of chromosomal band 5p15.33: a recurrent breakpoint region in mantle cell lymphoma involving the TERT–CLPTM1L locus. Leuk. Res. 37, 280–286 (2013).
Davis, C. F. et al. The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell 26, 319–330 (2014).
Peifer, M. et al. Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature 526, 700–704 (2015).
Barthel, F. P. et al. Systematic analysis of telomere length and somatic alterations in 31 cancer types. Nat. Genet. 49, 349–357 (2017).
Ryan, R. J. H. et al. Detection of enhancer-associated rearrangements reveals mechanisms of oncogene dysregulation in B-cell lymphoma. Cancer Discov. 5, 1058–1071 (2015).
Gan, W. et al. SPOP promotes ubiquitination and degradation of the ERG oncoprotein to suppress prostate cancer progression. Mol. Cell 59, 917–930 (2015).
An, J. et al. Truncated ERG oncoproteins from TMPRSS2–ERG fusions are resistant to SPOP-mediated proteasome degradation. Mol. Cell 59, 904–916 (2015).
Gröschel, S. et al. A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell 157, 369–381 (2014).
Drier, Y. et al. An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma. Nat. Genet. 48, 265–272 (2016).
Latysheva, N. S. & Babu, M. M. Discovering and understanding oncogenic gene fusions through data intensive computational approaches. Nucleic Acids Res. 44, 4487–4503 (2016).
Katainen, R. et al. CTCF/cohesin-binding sites are frequently mutated in cancer. Nat. Genet. 47, 818–821 (2015).
Kaiser, V. B., Taylor, M. S. & Semple, C. A. Mutational biases drive elevated rates of substitution at regulatory sites across cancer types. PLoS Genet. 12, e1006207 (2016).
Hnisz, D., Day, D. S. & Young, R. A. Insulated neighborhoods: structural and functional units of mammalian gene control. Cell 167, 1188–1200 (2016).
Liu, E. M. et al. Identification of cancer drivers at CTCF insulators in 1,962 whole genomes. Cell Syst. 8, 446–455.e8 (2019).
Hnisz, D. et al. Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science 351, 1454–1458 (2016).
Liu, Y. et al. Discovery of regulatory noncoding variants in individual cancer genomes by using cis-X. Nat. Genet. 52, 811–818 (2020).
Shi, J. et al. Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation. Genes Dev. 27, 2648–2662 (2013).
Herranz, D. et al. A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia. Nat. Med. 20, 1130–1137 (2014).
Zhang, X. et al. Somatic super-enhancer duplications and hotspot mutations lead to oncogenic activation of the KLF5 transcription factor. Cancer Discov. 8, 108–125 (2017).
Takeda, D. Y. et al. A somatically acquired enhancer of the androgen receptor is a noncoding driver in advanced prostate cancer. Cell 174, 422–432.e13 (2018).
Vogt, N. et al. Molecular structure of double-minute chromosomes bearing amplified copies of the epidermal growth factor receptor gene in gliomas. Proc. Natl Acad. Sci. USA 101, 11368–11373 (2004).
Kohl, N. E. et al. Transposition and amplification of oncogene-related sequences in human neuroblastomas. Cell 35, 359–367 (1983).
Koche, R. P. et al. Extrachromosomal circular DNA drives oncogenic genome remodeling in neuroblastoma. Nat. Genet. 52, 29–34 (2020).
Zhu, Y. et al. Oncogenic extrachromosomal DNA functions as mobile enhancers to globally amplify chromosomal transcription. Cancer Cell 39, 694–707.e7 (2021).
Hung, K. L. et al. ecDNA hubs drive cooperative intermolecular oncogene expression. Nature 600, 731–736 (2021).
Nurk, S. et al. The complete sequence of a human genome. Science 376, 44–53 (2022).
Tsao, M.-S. et al. Erlotinib in lung cancer — molecular and clinical predictors of outcome. N. Engl. J. Med. 353, 133–144 (2005).
Mohammad, H. P., Barbash, O. & Creasy, C. L. Targeting epigenetic modifications in cancer therapy: erasing the roadmap to cancer. Nat. Med. 25, 403–418 (2019).
Topper, M. J., Vaz, M., Marrone, K. A., Brahmer, J. R. & Baylin, S. B. The emerging role of epigenetic therapeutics in immuno-oncology. Nat. Rev. Clin. Oncol. 17, 75–90 (2020).
Viswanathan, S. R. et al. Structural alterations driving castration-resistant prostate cancer revealed by linked-read genome sequencing. Cell 174, 433–447.e19 (2018).
Logsdon, G. A., Vollger, M. R. & Eichler, E. E. Long-read human genome sequencing and its applications. Nat. Rev. Genet. 21, 597–614 (2020).
Chen, Z. et al. Ultralow-input single-tube linked-read library method enables short-read second-generation sequencing systems to routinely generate highly accurate and economical long-range sequencing information. Genome Res. 30, 898–909 (2020).
Luebeck, J. et al. AmpliconReconstructor integrates NGS and optical mapping to resolve the complex structures of focal amplifications. Nat. Commun. 11, 4374 (2020).
Chen, X. et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics 32, 1220–1222 (2016).
Chong, Z. et al. novoBreak: local assembly for breakpoint detection in cancer genomes. Nat. Methods 14, 65–67 (2017).
Hadi, K. et al. Distinct classes of complex structural variation uncovered across thousands of cancer genome graphs. Cell 183, 197–210.e32 (2020).
Deshpande, V. et al. Exploring the landscape of focal amplifications in cancer using AmpliconArchitect. Nat. Commun. 10, 392 (2019).
McPherson, A. W. et al. Correction to: ReMixT: clone-specific genomic structure estimation in cancer. Genome Biol. 18, 188 (2017).
Harewood, L. et al. Hi-C as a tool for precise detection and characterisation of chromosomal rearrangements and copy number variation in human tumours. Genome Biol. 18, 125 (2017).
Dixon, J. R. et al. Integrative detection and analysis of structural variation in cancer genomes. Nat. Genet. 50, 1388–1398 (2018).
Agnihotri, S. et al. The genomic landscape of schwannoma. Nat. Genet. 48, 1339–1348 (2016).
PCAWG Transcriptome Core Group. et al. Genomic basis for RNA alterations in cancer. Nature 578, 129–136 (2020).
McPherson, A. et al. deFuse: an algorithm for gene fusion discovery in tumor RNA-seq data. PLoS Comput. Biol. 7, e1001138 (2011).
Acknowledgements
This work was supported by the Independent Research Fund Denmark (0134-00265B; J.W. and N.S.), the German Research Foundation (DFG) (F.D.) and the National Institutes of Health (NIH), the Paediatric Brain Tumour Foundation, the Fund for Innovative Cancer Informatics and the Gray Matters Brain Cancer Foundation (R.B.).
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SVscape: http://svscape.com/
Glossary
- ‘A’ compartments
-
Cell type-specific megabase-scale organizations of the 3D genome associated with open chromatin and active transcript DNA.
- Breakage–fusion–bridge cycles
-
A mechanism of amplification in cancer genomes whereby chromosomes fuse due to telomere shortening and get broken apart during mitosis, leaving one daughter cell with extra copies of genes.
- Chromatin compartments
-
Subdivisions of chromosome territories divided into compartments with open and closed chromatin.
- Chromatin loop anchors
-
Protein complexes including CCCTC binding factor (CTCF) and cohesin that contribute to organizing the 3D structure of the genome.
- Chromoanasynthesis
-
A mechanism of complex structural variation (SV) generation due to template switching during replication.
- Chromoplexy
-
Chains of structural variations (SVs) involving multiple chromosomes.
- Chromosome territories
-
Discrete regions within the nucleus containing a specific chromosome.
- Chromothripsis
-
A mechanism of structural variation (SV) generation involving the shattering of a chromosome and random reassembly of DNA fragments, leading to a complex pattern of step-like copy number changes alternating between two, and sometimes three, states.
- Discordant reads
-
Paired-end sequencing reads where the distance separating the pair or their orientation differs from that expected.
- Driver events
-
Genetic variants resulting in increased evolutionary fitness of the affected cell.
- Evolutionary selection
-
In cancer, the process of enrichment of subclones with increased fitness within a clonal cell population.
- Extrachromosomal amplification
-
A small circular fragment of DNA that is randomly distributed during mitosis. Extrachromosomal amplifications can reach very high copy numbers, usually because they encode an oncogene and undergo positive selection.
- Hi-C
-
A proximity ligation-based sequencing technology that, in principle, allows the detection of all 3D interactions between DNA segments in the nucleus.
- Homologous recombination
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A relatively error-free DNA double-strand break (DSB) repair pathway involving a repair template (typically the homologous chromosome).
- Mechanistic biases
-
Differences in the background probability with which structural variations (SVs) will form at different loci in a particular cell type. This refers to the rate at which SVs form rather than the rate at which they are observed after undergoing evolutionary selection.
- Microhomology-mediated break-induced replication
-
A form of microhomology-mediated template switching during replication, which can lead to a complex structural variation (SV) pattern.
- Microhomology-mediated end-joining
-
A pathway for the repair of DNA double-strand breaks (DSBs) using microhomologous sequences at the break end to facilitate rejoining. Microhomology-mediated end-joining errors typically result in deletions.
- Non-homologous end-joining
-
A repair pathway for DNA double-strand breaks (DSBs) that does not involve a repair template. This can be more error-prone than homology-based repair mechanisms.
- Passenger events
-
Genetic variants with no positive effect on the evolutionary fitness of the affected cell that are nevertheless clonal in individual cancers, often due to positive selection resulting from driver events in the same cell.
- Phase separation
-
A phenomenon of decreased mixing between molecules because of differences in the intermolecular interactions. Most familiar from separation of mixed oil and water, phase separation is now understood to be a mechanism by which transcriptional complexes form.
- Punctuated evolution
-
Bursts of changes to the genome, with many variants acquired in one event, that can result in dramatical changes in evolutionary fitness. Punctuated evolution is often contrasted with the sequential acquisition and selection of individual variants in classic evolutionary theory.
- Split reads
-
A sequencing read that comprises different sequences that align to different loci in the reference genome.
- Templated insertions
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Structural variations (SVs) in which a sequence from a distant genomic locus is inserted between two break points.
- Topologically associated domains
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(TADs). Regions in the genome in the range of hundreds to thousands of kilobases that are separated by boundary elements and show higher 3D interaction frequencies within the TAD than between TADs.
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Dubois, F., Sidiropoulos, N., Weischenfeldt, J. et al. Structural variations in cancer and the 3D genome. Nat Rev Cancer 22, 533–546 (2022). https://doi.org/10.1038/s41568-022-00488-9
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DOI: https://doi.org/10.1038/s41568-022-00488-9
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