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Chromosome Structural Variation in Tumorigenesis: Mechanisms of Formation and Carcinogenesis Wen‑Jun Wang , Ling‑Yu Li and Jiu‑Wei Cui*

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Chromosome Structural Variation in Tumorigenesis: Mechanisms of Formation and Carcinogenesis Wen‑Jun Wang , Ling‑Yu Li and Jiu‑Wei Cui* Wang et al. Epigenetics & Chromatin (2020) 13:49 https://doi.org/10.1186/s13072-020-00371-7 Epigenetics & Chromatin REVIEW Open Access Chromosome structural variation in tumorigenesis: mechanisms of formation and carcinogenesis Wen‑Jun Wang , Ling‑Yu Li and Jiu‑Wei Cui* Abstract With the rapid development of next‑generation sequencing technology, chromosome structural variation has gradu‑ ally gained increased clinical signifcance in tumorigenesis. However, the molecular mechanism(s) underlying this structural variation remain poorly understood. A search of the literature shows that a three‑dimensional chromatin state plays a vital role in inducing structural variation and in the gene expression profles in tumorigenesis. Struc‑ tural variants may result in changes in copy number or deletions of coding sequences, as well as the perturbation of structural chromatin features, especially topological domains, and disruption of interactions between genes and their regulatory elements. This review focuses recent work aiming at elucidating how structural variations develop and misregulate oncogenes and tumor suppressors, to provide general insights into tumor formation mechanisms and to provide potential targets for future anticancer therapies. Keywords: Structural variation, Cancer, Translocation, Chromothripsis Introduction mutations and genomic classifcation has achieved over- Widespread chromosomal genomic rearrangement and whelming successes in hematology [2]. With the devel- point mutations are underlying hallmarks of the cancer opment of molecular biology techniques, many specifc genome. Next-generation sequencing technology has chromosomal structural variations (e.g., TMPRSS2-ERG enabled the detection of diverse patterns of genomic and EML4-ALK) have also been identifed in solid tumors changes in human somatic cells. Chromosome structural in recent years. variation, a vital kind of somatic mutation, is involved Te Pan-Cancer Analysis of Whole Genomes in the process of genomic rearrangement ranging from (PCAWG) Consortium of the International Cancer genes to entire chromosomes, and also afects gene Genome Consortium (ICGC) and Te Cancer Genome expression regulation. Chromosome structural variation Atlas (TCGA) collaborated to analyze structural variants, is a vital driver of oncogenesis and progression in both genomic breakpoint cluster regions, and gene expres- solid tumors and hematopoietic malignancies [1]. Te sion based on whole-genome sequencing data from 2658 combination of clinical features and structural variations cancers patients across 38 tumor types [3, 4]. However, provides the opportunity for cancer diagnosis, reason- our understanding of the underlying molecular mecha- able tumor subtype classifcation, prognosis, and preci- nisms of structural variation remains incomplete. None- sion treatment [2]. In fact, clinical testing for specifc theless, accumulating evidence suggests that changes in the three-dimensional (3D) conformational composi- tion or topologically associated domains (TADs) pro- *Correspondence: [email protected] vide a viable explanation for aberrant gene expression Cancer Center, The First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin, China in structural variation [5]. Moreover, the higher-order © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wang et al. Epigenetics & Chromatin (2020) 13:49 Page 2 of 17 chromatin structure as well as epigenetic modifcations Formation of structural variants (especially modifcations to histones and DNA) has grad- Accurate inference of specifc structural variants is cru- ually received interest as their vital roles in genome insta- cial for further characterization of the underlying molec- bility and DNA repair [6–9]. A greater understanding of ular process. It is quite difcult to recognize large-scale the specifc molecular mechanisms involved in the pro- complex chromosome rearrangements, which often cess of chromosomal rearrangement will provide invalu- afect multiple genes, simultaneously. Te constant able guidance for the design of precise cancer therapies. development of novel sequencing technologies and bio- Because driver mutations are causative, it is therapeutic informatic tools provides opportunities to explore the to target the function of resulting proteins or decrease associated epidemiology and mechanisms of rearrange- the occurrence of structural variation in tumors. ments. Several mechanisms have been thought to give Tis review builds on our increasingly sophisticated rise to genomic rearrangements involving DNA breakage, understanding of structural variation due to scientifc improper DSB repair, and long interspersed element-1 advances made over the last decade. Our goal is to sum- (LINE-1 or L1)-mediated retrotransposition. marize the mechanisms of structural variations in tumo- rigenesis from both molecular mechanisms and spatial DNA breakage structure, to convey a novel perspective for clinical thera- Simple DNA breakage pies and resistance prevention. Te patterns of chromosome rearrangement are infu- enced by the cause and position of DSBs as well as the specifc mechanisms involved in the repair. DSBs are the Categorization of structural variants most lethal type of DNA damage and are important inter- Although the patterns of structural variants are diferent, mediates in the process of generating structural variants. their formation is commonly involved in the occurrence Exogenous mutagens (e.g., chemicals, ionizing radiation, of DNA double-strand breaks (DSB) and improper repair ultraviolet light, and viral infections) or cell-intrinsic pro- or rejoining of broken chromosomes [10]. Te number cesses (e.g., oxidative metabolism or replication stress) of breakpoints involved and the rearrangement patterns that occur throughout life often produce somatic muta- are two signifcant features of structural variants. Li et al. tions [2, 12, 13]. Endogenous DSBs mainly occur during have suggested that these structural variants should be fundamental processes, especially replication and tran- categorized according to the two aforementioned factors scription (reviewed by Cannan et al. and Bouwman et al.) [1]. In terms of the number of breakpoints, structural [14, 15] variants can be divided into simple (i.e., deletions, tan- Activation-induced cytidine deaminase (AID) and dem duplications, reciprocal inversions, and transloca- recombination-activating genes (RAGs) can both gen- tions) or complex structural variants (i.e., chromothripsis erate of-target DNA cleavage, thereby contributing to and chromoplexy among others). Inversions can be fur- genomic rearrangements in cancer [16, 17]. AID accounts ther divided into paracentric and pericentric inversions. for genetic changes (including somatic hypermutation Deletions are the most common and simplest structural and class-switch recombination [CSR]) in the Ig gene in variant, followed by tandem duplications and unbalanced activated B cells. Interestingly, however, AID can target translocations [1]. non-Ig genes, leading to DNA DSBs or mutations [17]. Meanwhile, the rearrangement patterns include ‘cut- RAG, a lymphoid-specifc endonuclease, participates in and-paste’ (e.g., deletions, reciprocal inversions, chro- V(D)J recombination, which accounts for antigen recep- mothripsis, and chromoplexy) or ‘copy-and-paste’ (e.g., tor diversity [16, 18]. Type II topoisomerase (TOP2) pro- tandem duplications, templated insertions, and local teins, which normally solve topological issues through n-jump) [1]. Te templated insertions refer to a string DSBs, can generate several known translocation break- of inserted segments copied from one or more genomic points in leukemia and prostate cancer (PCa) resulting in templates. Te local n-jump is a cluster of n structural MLL and TMPRSS2-ERG translocations, respectively [19, variations located at a single genomic region accom- 20]. panied by copy number alterations (CNAs) as well as Telomere dysfunction can also cause genome instability inverted and noninverted junctions. Breakage-fusion- which may trigger oncogenic events [11]. During DNA bridge events are more complex ‘cut-and-paste’ processes replication, chromosomes with uncapped telomeres are that produce structural variants and are caused by cycles recognized as DNA double-strand ‘breaks’ resulting in of DNA breakage, end-to-end sister chromatid fusions, the generation of end-to-end fusions and subsequently, mitotic bridges, and further DNA breakage. Such events a dicentric chromosome.
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