Chromothripsis represents a mechanism of massive chromosome shattering and reassembly leading to the formation of derivative chromosomes with abnormal functions and expression. It has been observed in many cancer types, importantly, including chronic lymphocytic leukemia (CLL). Due to the associated chromosomal rearrangements, it has a significant impact on the pathophysiology of the disease. Recent studies have suggested that chromothripsis may be more common than initially inferred, especially in CLL cases with adverse clinical outcome. Here, we review the main features of chromothripsis, the challenges of its assessment, and the potential benefit of its detection. We summarize recent findings of chromothripsis occurrence across hematological malignancies and address its causes and consequences in the context of CLL clinical features, as well as chromothripsis-related molecular abnormalities described in published CLL studies. Furthermore, we discuss the use of the current knowledge about genome functions associated with chromothripsis in the optimization of treatment strategies in CLL.

Center of Molecular Medicine Central European Institute of Technology Masaryk University Brno Czechia

Department of Internal Medicine Hematology and Oncology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czechia

Institute of Medical Genetics and Genomics University Hospital Brno and Masaryk University Brno Czechia

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Baliakas P, Jeromin S, Iskas M, Puiggros A, Plevova K, Nguyen-Khac F, et al. . Cytogenetic Complexity in Chronic Lymphocytic Leukemia: Definitions, Associations, and Clinical Impact. Blood (2019) 133:1205–16. doi: 10.1182/blood-2018-09-873083 PubMed DOI PMC

Leeksma AC, Baliakas P, Moysiadis T, Puiggros A, Plevova K, van der Kevie-Kersemaekers A-M, et al. . Genomic Arrays Identify High-Risk Chronic Lymphocytic Leukemia With Genomic Complexity: A Multi-Center Study. Haematologica (2021) 106:87–97. doi: 10.3324/haematol.2019.239947 PubMed DOI PMC

Edelmann J, Holzmann K, Miller F, Winkler D, Bühler A, Zenz T, et al. . High-Resolution Genomic Profiling of Chronic Lymphocytic Leukemia Reveals New Recurrent Genomic Alterations. Blood (2012) 120:4783–94. doi: 10.1182/blood-2012-04-423517 PubMed DOI

Malek SN. The Biology and Clinical Significance of Acquired Genomic Copy Number Aberrations and Recurrent Gene Mutations in Chronic Lymphocytic Leukemia. Oncogene (2013) 32:2805–17. doi: 10.1038/onc.2012.411 PubMed DOI PMC

Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, et al. . Massive Genomic Rearrangement Acquired in a Single Catastrophic Event During Cancer Development. Cell (2011) 144:27–40. doi: 10.1016/j.cell.2010.11.055 PubMed DOI PMC

Zhang C-Z, Leibowitz ML, Pellman D. Chromothripsis and Beyond: Rapid Genome Evolution From Complex Chromosomal Rearrangements. Genes Dev (2013) 27:2513–30. doi: 10.1101/gad.229559.113 PubMed DOI PMC

Korbel JO, Campbell PJ. Criteria for Inference of Chromothripsis in Cancer Genomes. Cell (2013) 152:1226–36. doi: 10.1016/j.cell.2013.02.023 PubMed DOI

Leibowitz ML, Zhang C-Z, Pellman D. Chromothripsis: A New Mechanism for Rapid Karyotype Evolution. Annu Rev Genet (2015) 49:183–211. doi: 10.1146/annurev-genet-120213-092228 PubMed DOI

Umbreit NT, Zhang C-Z, Lynch LD, Blaine LJ, Cheng AM, Tourdot R, et al. . Mechanisms Generating Cancer Genome Complexity From a Single Cell Division Error. Science (2020) 368:eaba0712. doi: 10.1126/science.aba0712 PubMed DOI PMC

Kloosterman WP, Hoogstraat M, Paling O, Tavakoli-Yaraki M, Renkens I, Vermaat JS, et al. . Chromothripsis Is a Common Mechanism Driving Genomic Rearrangements in Primary and Metastatic Colorectal Cancer. Genome Biol (2011) 12:R103. doi: 10.1186/gb-2011-12-10-r103 PubMed DOI PMC

Magrangeas F, Avet-Loiseau H, Munshi NC, Minvielle S. Chromothripsis Identifies a Rare and Aggressive Entity Among Newly Diagnosed Multiple Myeloma Patients. Blood (2011) 118:675–8. doi: 10.1182/blood-2011-03-344069 PubMed DOI PMC

Northcott PA, Shih DJH, Peacock J, Garzia L, Morrissy AS, Zichner T, et al. . Subgroup-Specific Structural Variation Across 1,000 Medulloblastoma Genomes. Nature (2012) 488:49–56. doi: 10.1038/nature11327 PubMed DOI PMC

Hirsch D, Kemmerling R, Davis S, Camps J, Meltzer PS, Ried T, et al. . Chromothripsis and Focal Copy Number Alterations Determine Poor Outcome in Malignant Melanoma. Cancer Res (2013) 73:1454–60. doi: 10.1158/0008-5472.CAN-12-0928 PubMed DOI PMC

Molenaar JJ, Koster J, Zwijnenburg DA, van Sluis P, Valentijn LJ, van der Ploeg I, et al. . Sequencing of Neuroblastoma Identifies Chromothripsis and Defects in Neuritogenesis Genes. Nature (2012) 483:589–93. doi: 10.1038/nature10910 PubMed DOI

Rausch T, Jones DTW, Zapatka M, Stütz AM, Zichner T, Weischenfeldt J, et al. . Genome Sequencing of Pediatric Medulloblastoma Links Catastrophic DNA Rearrangements With TP53 Mutations. Cell (2012) 148:59–71. doi: 10.1016/j.cell.2011.12.013 PubMed DOI PMC

Pei J, Jhanwar SC, Testa JR. Chromothripsis in a Case of TP53-Deficient Chronic Lymphocytic Leukemia. Leuk Res Rep (2012) 1:4–6. doi: 10.1016/j.lrr.2012.09.001 PubMed DOI PMC

Bassaganyas L, Beà S, Escaramís G, Tornador C, Salaverria I, Zapata L, et al. . Sporadic and Reversible Chromothripsis in Chronic Lymphocytic Leukemia Revealed by Longitudinal Genomic Analysis. Leukemia (2013) 27:2376–9. doi: 10.1038/leu.2013.127 PubMed DOI PMC

Salaverria I, Martín-Garcia D, López C, Clot G, García-Aragonés M, Navarro A, et al. . Detection of Chromothripsis-Like Patterns With a Custom Array Platform for Chronic Lymphocytic Leukemia. Genes Chromosomes Cancer (2015) 54:668–80. doi: 10.1002/gcc.22277 PubMed DOI PMC

Tan L, Xu L-H, Liu H-B, Yang S-J. Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia With Chromothripsis in an Old Woman. Chin Med J (Engl) (2015) 128:985–7. doi: 10.4103/0366-6999.154329 PubMed DOI PMC

Parker H, Rose-Zerilli MJJ, Larrayoz M, Clifford R, Edelmann J, Blakemore S, et al. . Genomic Disruption of the Histone Methyltransferase SETD2 in Chronic Lymphocytic Leukaemia. Leukemia (2016) 30:2179–86. doi: 10.1038/leu.2016.134 PubMed DOI PMC

Cortés-Ciriano I, Lee JJ-K, Xi R, Jain D, Jung YL, Yang L, et al. . Comprehensive Analysis of Chromothripsis in 2,658 Human Cancers Using Whole-Genome Sequencing. Nat Genet (2020) 52:331–41. doi: 10.1038/s41588-019-0576-7 PubMed DOI PMC

Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV, Pan Y, et al. . DNA Breaks and Chromosome Pulverization From Errors in Mitosis. Nature (2012) 482:53–8. doi: 10.1038/nature10802 PubMed DOI PMC

Maciejowski J, Li Y, Bosco N, Campbell PJ, de Lange T. Chromothripsis and Kataegis Induced by Telomere Crisis. Cell (2015) 163:1641–54. doi: 10.1016/j.cell.2015.11.054 PubMed DOI PMC

Ramos-Campoy S, Puiggros A, Beà S, Bougeon S, Larráyoz MJ, Costa D, et al. . Chromosome Banding Analysis and Genomic Microarrays Are Both Useful But Not Equivalent Methods for Genomic Complexity Risk Stratification in Chronic Lymphocytic Leukemia Patients. Haematologica (2020). doi: 10.3324/haematol.2020.274456 PubMed DOI PMC

Hynst J, Plevova K, Radova L, Bystry V, Pal K, Pospisilova S. Bioinformatic Pipelines for Whole Transcriptome Sequencing Data Exploitation in Leukemia Patients With Complex Structural Variants. PeerJ (2019) 7:e7071. doi: 10.7717/peerj.7071 PubMed DOI PMC

Kim T-M, Xi R, Luquette LJ, Park RW, Johnson MD, Park PJ. Functional Genomic Analysis of Chromosomal Aberrations in a Compendium of 8000 Cancer Genomes. Genome Res (2013) 23:217–27. doi: 10.1101/gr.140301.112 PubMed DOI PMC

Stevens-Kroef M, Weghuis DO, Croockewit S, Derksen L, Hooijer J, ElIdrissi-Zaynoun N, et al. . High Detection Rate of Clinically Relevant Genomic Abnormalities in Plasma Cells Enriched From Patients With Multiple Myeloma. Genes Chromosomes Cancer (2012) 51:997–1006. doi: 10.1002/gcc.21982 PubMed DOI

Zemanova Z, Michalova K, Buryova H, Brezinova J, Kostylkova K, Bystricka D, et al. . Involvement of Deleted Chromosome 5 in Complex Chromosomal Aberrations in Newly Diagnosed Myelodysplastic Syndromes (MDS) Is Correlated With Extremely Adverse Prognosis. Leukemia Res (2014) 38:537–44. doi: 10.1016/j.leukres.2014.01.012 PubMed DOI

Abáigar M, Robledo C, Benito R, Ramos F, Díez-Campelo M, Hermosín L, et al. . Chromothripsis Is a Recurrent Genomic Abnormality in High-Risk Myelodysplastic Syndromes. PloS One (2016) 11:e0164370. doi: 10.1371/journal.pone.0164370 PubMed DOI PMC

Bochtler T, Granzow M, Stölzel F, Kunz C, Mohr B, Kartal-Kaess M, et al. . Marker Chromosomes can Arise From Chromothripsis and Predict Adverse Prognosis in Acute Myeloid Leukemia. Blood (2017) 129:1333–42. doi: 10.1182/blood-2016-09-738161 PubMed DOI

Rücker FG, Dolnik A, Blätte TJ, Teleanu V, Ernst A, Thol F, et al. . Chromothripsis is Linked to TP53 Alteration, Cell Cycle Impairment, and Dismal Outcome in Acute Myeloid Leukemia With Complex Karyotype. Haematologica (2018) 103:e17–20. doi: 10.3324/haematol.2017.180497 PubMed DOI PMC

Fontana MC, Marconi G, Feenstra JDM, Fonzi E, Papayannidis C, Ghelli Luserna di Rorá A, et al. . Chromothripsis in Acute Myeloid Leukemia: Biological Features and Impact on Survival. Leukemia (2018) 32:1609–20. doi: 10.1038/s41375-018-0035-y PubMed DOI PMC

MacKinnon RN, Campbell LJ. Chromothripsis Under the Microscope: A Cytogenetic Perspective of Two Cases of AML With Catastrophic Chromosome Rearrangement. Cancer Genet (2013) 206:238–51. doi: 10.1016/j.cancergen.2013.05.021 PubMed DOI

Forero-Castro M, Robledo C, Benito R, Abáigar M, África Martín A, Arefi M, et al. . Genome-Wide DNA Copy Number Analysis of Acute Lymphoblastic Leukemia Identifies New Genetic Markers Associated With Clinical Outcome. PloS One (2016) 11:e0148972. doi: 10.1371/journal.pone.0148972 PubMed DOI PMC

Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D, et al. . The Genetic Basis of Early T-Cell Precursor Acute Lymphoblastic Leukaemia. Nature (2012) 481:157–63. doi: 10.1038/nature10725 PubMed DOI PMC

Li Y, Schwab C, Ryan S, Papaemmanuil E, Robinson HM, Jacobs P, et al. . Constitutional and Somatic Rearrangement of Chromosome 21 in Acute Lymphoblastic Leukaemia. Nature (2014) 508:98–102. doi: 10.1038/nature13115 PubMed DOI PMC

Ratnaparkhe M, Hlevnjak M, Kolb T, Jauch A, Maass KK, Devens F, et al. . Genomic Profiling of Acute Lymphoblastic Leukemia in Ataxia Telangiectasia Patients Reveals Tight Link Between ATM Mutations and Chromothripsis. Leukemia (2017) 31:2048–56. doi: 10.1038/leu.2017.55 PubMed DOI

Puente XS, Beà S, Valdés-Mas R, Villamor N, Gutiérrez-Abril J, Martín-Subero JI, et al. . Non-Coding Recurrent Mutations in Chronic Lymphocytic Leukaemia. Nature (2015) 526:519–24. doi: 10.1038/nature14666 PubMed DOI

Burns A, Alsolami R, Becq J, Stamatopoulos B, Timbs A, Bruce D, et al. . Whole-Genome Sequencing of Chronic Lymphocytic Leukaemia Reveals Distinct Differences in the Mutational Landscape Between IgHVmut and IgHVunmut Subgroups. Leukemia (2018) 32:332–42. doi: 10.1038/leu.2017.177 PubMed DOI PMC

Chudasama P, Mughal SS, Sanders MA, Hübschmann D, Chung I, Deeg KI, et al. . Integrative Genomic and Transcriptomic Analysis of Leiomyosarcoma. Nat Commun (2018) 9:144. doi: 10.1038/s41467-017-02602-0 PubMed DOI PMC

ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-Cancer Analysis of Whole Genomes. Nature (2020) 578:82–93. doi: 10.1038/s41586-020-1969-6 PubMed DOI PMC

Barrett T, Troup DB, Wilhite SE, Ledoux P, Rudnev D, Evangelista C, et al. . NCBI GEO: Archive for High-Throughput Functional Genomic Data. Nucleic Acids Res (2009) 37:D885–890. doi: 10.1093/nar/gkn764 PubMed DOI PMC

Voronina N, Wong JKL, Hübschmann D, Hlevnjak M, Uhrig S, Heilig CE, et al. . The Landscape of Chromothripsis Across Adult Cancer Types. Nat Commun (2020) 11:2320. doi: 10.1038/s41467-020-16134-7 PubMed DOI PMC

Horak P, Klink B, Heining C, Gröschel S, Hutter B, Fröhlich M, et al. . Precision Oncology Based on Omics Data: The NCT Heidelberg Experience. Int J Cancer (2017) 141:877–86. doi: 10.1002/ijc.30828 PubMed DOI

Li Y, Buijs-Gladdines JGCAM, Canté-Barrett K, Stubbs AP, Vroegindeweij EM, Smits WK, et al. . IL-7 Receptor Mutations and Steroid Resistance in Pediatric T Cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study. PloS Med (2016) 13:e1002200. doi: 10.1371/journal.pmed.1002200 PubMed DOI PMC

Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, et al. . Genomic Aberrations and Survival in Chronic Lymphocytic Leukemia. N Engl J Med (2000) 343:1910–6. doi: 10.1056/NEJM200012283432602 PubMed DOI

Stilgenbauer S, Schnaiter A, Paschka P, Zenz T, Rossi M, Döhner K, et al. . Gene Mutations and Treatment Outcome in Chronic Lymphocytic Leukemia: Results From the CLL8 Trial. Blood (2014) 123:3247–54. doi: 10.1182/blood-2014-01-546150 PubMed DOI

Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. . Guidelines for the Diagnosis and Treatment of Chronic Lymphocytic Leukemia: A Report From the International Workshop on Chronic Lymphocytic Leukemia Updating the National Cancer Institute–Working Group 1996 Guidelines. Blood (2008) 111:5446–56. doi: 10.1182/blood-2007-06-093906 PubMed DOI PMC

Rossi D, Khiabanian H, Spina V, Ciardullo C, Bruscaggin A, Famà R, et al. . Clinical Impact of Small TP53 Mutated Subclones in Chronic Lymphocytic Leukemia. Blood (2014) 123:2139–47. doi: 10.1182/blood-2013-11-539726 PubMed DOI PMC

International CLL-IPI Working Group. An International Prognostic Index for Patients With Chronic Lymphocytic Leukaemia (CLL-IPI): A Meta-Analysis of Individual Patient Data. Lancet Oncol (2016) 17:779–90. doi: 10.1016/S1470-2045(16)30029-8 PubMed DOI

Malcikova J, Stano-Kozubik K, Tichy B, Kantorova B, Pavlova S, Tom N, et al. . Detailed Analysis of Therapy-Driven Clonal Evolution of TP53 Mutations in Chronic Lymphocytic Leukemia. Leukemia (2015) 29:877–85. doi: 10.1038/leu.2014.297 PubMed DOI PMC

Ma X, Liu Y, Liu Y, Alexandrov LB, Edmonson MN, Gawad C, et al. . Pan-Cancer Genome and Transcriptome Analyses of 1,699 Paediatric Leukaemias and Solid Tumours. Nature (2018) 555:371–6. doi: 10.1038/nature25795 PubMed DOI PMC

Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D, et al. . COSMIC: Mining Complete Cancer Genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res (2011) 39:D945–50. doi: 10.1093/nar/gkq929 PubMed DOI PMC

Vogelstein B, Lane D, Levine AJ. Surfing the P53 Network. Nature (2000) 408:307–10. doi: 10.1038/35042675 PubMed DOI

Finn WG, Kay NE, Kroft SH, Church S, Peterson LC. Secondary Abnormalities of Chromosome 6q in B-Cell Chronic Lymphocytic Leukemia: A Sequential Study of Karyotypic Instability in 51 Patients. Am J Hematol (1998) 59:223–9. doi: 10.1002/(sici)1096-8652(199811)59:3<223::aid-ajh7>3.0.co;2-y PubMed DOI

Forconi F, Rinaldi A, Kwee I, Sozzi E, Raspadori D, Rancoita PMV, et al. . Genome-Wide DNA Analysis Identifies Recurrent Imbalances Predicting Outcome in Chronic Lymphocytic Leukaemia With 17p Deletion. Br J Haematol (2008) 143:532–6. doi: 10.1111/j.1365-2141.2008.07373.x PubMed DOI

Brown JR, Hanna M, Tesar B, Werner L, Pochet N, Asara JM, et al. . Integrative Genomic Analysis Implicates Gain of PIK3CA at 3q26 and MYC at 8q24 in Chronic Lymphocytic Leukemia. Clin Cancer Res (2012) 18:3791–802. doi: 10.1158/1078-0432.CCR-11-2342 PubMed DOI PMC

Kume K, Iizumi Y, Shimada M, Ito Y, Kishi T, Yamaguchi Y, et al. . Role of N-End Rule Ubiquitin Ligases UBR1 and UBR2 in Regulating the leucine-mTOR Signaling Pathway. Genes Cells (2010) 15:339–49. doi: 10.1111/j.1365-2443.2010.01385.x PubMed DOI

Jebaraj BMC, Stilgenbauer S. Telomere Dysfunction in Chronic Lymphocytic Leukemia. Front Oncol (2021) 0:612665. doi: 10.3389/fonc.2020.612665 PubMed DOI PMC

Olbertova H, Plevova K, Stranska K, Pospisilova S. Telomere Dynamics in Adult Hematological Malignancies. BioMed Pap Med Fac Univ Palacky Olomouc Czech Repub (2019) 163:1–7. doi: 10.5507/bp.2018.084 PubMed DOI

Sharpless NE, Sherr CJ. Forging a Signature of In Vivo Senescence. Nat Rev Cancer (2015) 15:397–408. doi: 10.1038/nrc3960 PubMed DOI

Falandry C, Bonnefoy M, Freyer G, Gilson E. Biology of Cancer and Aging: A Complex Association With Cellular Senescence. J Clin Oncol (2014) 32:2604–10. doi: 10.1200/JCO.2014.55.1432 PubMed DOI

Damle RN, Batliwalla FM, Ghiotto F, Valetto A, Albesiano E, Sison C, et al. . Telomere Length and Telomerase Activity Delineate Distinctive Replicative Features of the B-CLL Subgroups Defined by Immunoglobulin V Gene Mutations. Blood (2004) 103:375–82. doi: 10.1182/blood-2003-04-1345 PubMed DOI

Roos G, Kröber A, Grabowski P, Kienle D, Bühler A, Döhner H, et al. . Short Telomeres Are Associated With Genetic Complexity, High-Risk Genomic Aberrations, and Short Survival in Chronic Lymphocytic Leukemia. Blood (2008) 111:2246–52. doi: 10.1182/blood-2007-05-092759 PubMed DOI

Rossi D, Lobetti Bodoni C, Genuardi E, Monitillo L, Drandi D, Cerri M, et al. . Telomere Length Is an Independent Predictor of Survival, Treatment Requirement and Richter’s Syndrome Transformation in Chronic Lymphocytic Leukemia. Leukemia (2009) 23:1062–72. doi: 10.1038/leu.2008.399 PubMed DOI

Bechter OE, Eisterer W, Pall G, Hilbe W, Kühr T, Thaler J. Telomere Length and Telomerase Activity Predict Survival in Patients With B Cell Chronic Lymphocytic Leukemia. Cancer Res (1998) 58:4918–22. PubMed

Damle RN, Temburni S, Banapour T, Paul S, Mongini PKA, Allen SL, et al. . Chiorazzi N. T-Cell Independent, B-Cell Receptor-Mediated Induction of Telomerase Activity Differs Among IGHV Mutation-Based Subgroups of Chronic Lymphocytic Leukemia Patients. Blood (2012) 120:2438–49. doi: 10.1182/blood-2012-02-409110 PubMed DOI PMC

Lin TT, Letsolo BT, Jones RE, Rowson J, Pratt G, Hewamana S, et al. . Telomere Dysfunction and Fusion During the Progression of Chronic Lymphocytic Leukemia: Evidence for a Telomere Crisis. Blood (2010) 116:1899–907. doi: 10.1182/blood-2010-02-272104 PubMed DOI

Lo AWI, Sabatier L, Fouladi B, Pottier G, Ricoul M, Murnane JP. DNA Amplification by Breakage/Fusion/Bridge Cycles Initiated by Spontaneous Telomere Loss in a Human Cancer Cell Line. Neoplasia (2002) 4:531–8. doi: 10.1038/sj.neo.7900267 PubMed DOI PMC

Ernst A, Jones DTW, Maass KK, Rode A, Deeg KI, Jebaraj BMC, et al. . Telomere Dysfunction and Chromothripsis. Int J Cancer (2016) 138:2905–14. doi: 10.1002/ijc.30033 PubMed DOI

Dos Santos P, Panero J, Palau Nagore V, Stanganelli C, Bezares RF, Slavutsky I. Telomere Shortening Associated With Increased Genomic Complexity in Chronic Lymphocytic Leukemia. Tumour Biol (2015) 36:8317–24. doi: 10.1007/s13277-015-3556-2 PubMed DOI

Thomay K, Fedder C, Hofmann W, Kreipe H, Stadler M, Titgemeyer J, et al. . Telomere Shortening, TP53 Mutations and Deletions in Chronic Lymphocytic Leukemia Result in Increased Chromosomal Instability and Breakpoint Clustering in Heterochromatic Regions. Ann Hematol (2017) 96:1493–500. doi: 10.1007/s00277-017-3055-1 PubMed DOI

Jebaraj BMC, Tausch E, Landau DA, Bahlo J, Robrecht S, Taylor-Weiner AN, et al. . Short Telomeres Are Associated With Inferior Outcome, Genomic Complexity, and Clonal Evolution in Chronic Lymphocytic Leukemia. Leukemia (2019) 33:2183–94. doi: 10.1038/s41375-019-0446-4 PubMed DOI PMC

Mansouri L, Grabowski P, Degerman S, Svenson U, Gunnarsson R, Cahill N, et al. . Short Telomere Length Is Associated With NOTCH1/SF3B1/TP53 Aberrations and Poor Outcome in Newly Diagnosed Chronic Lymphocytic Leukemia Patients. Am J Hematol (2013) 88:647–51. doi: 10.1002/ajh.23466 PubMed DOI

Norris K, Hillmen P, Rawstron A, Hills R, Baird DM, Fegan CD, et al. . Telomere Length Predicts for Outcome to FCR Chemotherapy in CLL. Leukemia (2019) 33:1953–63. doi: 10.1038/s41375-019-0389-9 PubMed DOI PMC

Strefford JC, Kadalayil L, Forster J, Rose-Zerilli MJJ, Parker A, Lin TT, et al. . Telomere Length Predicts Progression and Overall Survival in Chronic Lymphocytic Leukemia: Data From the UK LRF CLL4 Trial. Leukemia (2015) 29:2411–4. doi: 10.1038/leu.2015.217 PubMed DOI PMC

Song DY, Kim J-A, Jeong D, Yun J, Kim S-M, Lim K, et al. . Telomere Length and Its Correlation With Gene Mutations in Chronic Lymphocytic Leukemia in a Korean Population. PloS One (2019) 14:e0220177. doi: 10.1371/journal.pone.0220177 PubMed DOI PMC

Britt-Compton B, Lin TT, Ahmed G, Weston V, Jones RE, Fegan C, et al. . Extreme Telomere Erosion in ATM-Mutated and 11q-Deleted CLL Patients is Independent of Disease Stage. Leukemia (2012) 26:826–30. doi: 10.1038/leu.2011.281 PubMed DOI

Steinbrecher D, Jebaraj BMC, Schneider C, Edelmann J, Cymbalista F, Leblond V, et al. . Telomere Length in Poor-Risk Chronic Lymphocytic Leukemia: Associations With Disease Characteristics and Outcome. Leuk Lymphoma (2018) 59:1614–23. doi: 10.1080/10428194.2017.1390236 PubMed DOI

Ivkov R, Bunz F. Pathways to Chromothripsis. Cell Cycle (2015) 14:2886–90. doi: 10.1080/15384101.2015.1068483 PubMed DOI PMC

Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. . PD-1 Blockade in Tumors With Mismatch-Repair Deficiency. N Engl J Med (2015) 372:2509–20. doi: 10.1056/NEJMoa1500596 PubMed DOI PMC

Mansfield AS, Peikert T, Smadbeck JB, Udell JBM, Garcia-Rivera E, Elsbernd L, et al. . Neoantigenic Potential of Complex Chromosomal Rearrangements in Mesothelioma. J Thorac Oncol (2019) 14:276–87. doi: 10.1016/j.jtho.2018.10.001 PubMed DOI PMC

Singh ZN, Richards S, El Chaer F, Duong VH, Gudipati MA, Waters EO, et al. . Cryptic ETV6–PDGFRB Fusion in a Highly Complex Rearrangement of Chromosomes 1, 5, and 12 Due to a Chromothripsis-Like Event in a Myelodysplastic Syndrome/Myeloproliferative Neoplasm. Leukemia Lymphoma (2019) 60:1304–7. doi: 10.1080/10428194.2018.1480774 PubMed DOI

Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. . The 2016 Revision to the World Health Organization Classification of Myeloid Neoplasms and Acute Leukemia. Blood (2016) 127:2391–405. doi: 10.1182/blood-2016-03-643544 PubMed DOI

O’Neil NJ, Bailey ML, Hieter P. Synthetic Lethality and Cancer. Nat Rev Genet (2017) 18:613–23. doi: 10.1038/nrg.2017.47 PubMed DOI

Lord CJ, Ashworth A. The DNA Damage Response and Cancer Therapy. Nature (2012) 481:287–94. doi: 10.1038/nature10760 PubMed DOI