Abstract

Chromosomal mis-segregation events in cancer are increasingly being recognized as driving factors behind the pathology. Despite the existence of several checkpoints in the cell to monitor and stop events leading to cancerous growth newer research data are discovering several forms of structural variations in wide range of cancers. Chromothripsis, characterized by tens to hundreds of structural rearrangements resulting in intricate changes to one or a few chromosomes, has become a remarkable and mysterious occurrence in biology. The resulting derivative chromosome is very different from its original structure, and it has been found to have a unique mutation signature in a number of malignancies. The present review aims to summarize the current knowledge in this area with sections dedicated to Genomic instability and chromothripsis, causes and consequences and Chromosome dynamics and chromothripsis. Last two sections are directed towards the spectrum of diseases affected by chromothripsis and the therapeutic approaches. The topic offers several useful insights into the biology of genome stability and chromosomal dynamics. Detailed cell biology and live-cell studies, and omics research will help uncover the genotype-phenotype relationship and pave way for therapeutic interventions.

• 1.   Adam, S., Rossi, S.E., Moatti, N., et al. (2021). The CIP2A–TOPBP1 axis safeguards chromosome stability and is a synthetic lethal target for BRCAmutated cancer. Nature Cancer 2, 1357– 1371. DOI: 10.1038/s43018-021-00266-w
• 2.   Alonso, S., & Dow, L. E. (2021). Engineering chromosome rearrangements in cancer. Disease Models & Mechanisms, 14(9), dmm049078. doi: https://doi.org/10.1242/dmm.049078
• 3.   Audibert, S., & Soutoglou, E. (2023). Guiding DNA repair at the nuclear periphery. nature cell biology, 25(7), 928-930. DOI: 10.1038/ s41556-023-01164-2
• 4.   Bakhoum, S. F., & Cantley, L. C. (2018). The multifaceted role of chromosomal instability in cancer and its microenvironment. Cell, 174(6), 1347-1360. DOI: 10.1016/j.cell.2018.08.027
• 5.   Bakhoum, S. F., Ngo, B., Laughney, A. M., Cavallo, J. A., Murphy, C. J., Ly, P., & Cantley, L. C. (2018). Chromosomal instability drives metastasis through a cytosolic DNA response. Nature, 553(7689), 467-472. DOI: 10.1038/nature25432
• 6.   Bakhoum, S.F., and Cantley, L.C. (2018). The multifaceted role of chromosomal instability in cancer and its microenvironment. Cell 174, 1347–1360. DOI: 10.1016/j.cell.2018.08.027
• 7.   Bakhoum, S.F., and Cantley, L.C. (2018). The multifaceted role of chromosomal instability in cancer and its microenvironment. Cell 174, 1347–1360. DOI: 10.1016/j.cell.2018.08.027
• 8.   Beernaert, B., & Parkes, E. E. (2023). cGAS– STING signalling in cancer: striking a balance with chromosomal instability. Biochemical Society Transactions, 51(2), 539-555. DOI: 10.1042/BST20220838
• 9.   Bochtler, T., Kartal-Kaess, M., Granzow, M., Hielscher, T., Cosenza, M. R., Herold-Mende, C., ... & Krämer, A. (2019). Micronucleus formation in human cancer cells is biased by chromosome size. Genes, Chromosomes and Cancer, 58(6), 392-395.DOI: 10.1002/gcc.22707
• 10.   Bodrug, T., Welsh, K. A., Hinkle, M., Emanuele, M. J., & Brown, N. G. (2021). Intricate regulatory mechanisms of the anaphasepromoting complex/cyclosome and its role in chromatin regulation. Frontiers in Cell and Developmental Biology, 9, 687515.doi: 10.3389/ fcell.2021.687515.
• 11.   Bolhaqueiro, A. C., Ponsioen, B., Bakker, B., Klaasen, S. J., Kucukkose, E., van Jaarsveld, R. H., ... & Kops, G. J. (2019). Ongoing chromosomal instability and karyotype evolution in human colorectal cancer organoids. Nature genetics, 51(5), 824-834. DOI: 10.1038/s41588-019-0399-6
• 12.   Bolkestein, M., Wong, J. K., Thewes, V., Körber, V., Hlevnjak, M., Elgaafary, S., ... & Ernst, A. (2020). Chromothripsis in human breast cancer. Cancer research, 80(22), 4918- 4931.DOI: 10.1158/0008-5472.CAN-20-1920
• 13.   Bradshaw, R. A., & Stahl, P. D. (2015). Encyclopedia of cell biology. Academic Press.
• 14.   Cai, H., Kumar, N., Bagheri, H. C., von Mering, C., Robinson, M. D., & Baudis, M. (2014). Chromothripsis-like patterns are recurring but heterogeneously distributed features in a survey of 22,347 cancer genome screens. BMC genomics, 15(1), 82. DOI: 10.1186/1471-2164-15- 82
• 15.   Cancer Genome Atlas Research Network. (2014). Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202– 209. DOI: 10.1038/nature13480
• 16.   Cannan, W. J., & Pederson, D. S. (2016). Mechanisms and consequences of double-strand DNA break formation in chromatin. Journal of cellular physiology, 231(1), 3-14. DOI: 10.1002/jcp.25048
• 17.   Cannan, W.J., and Pederson, D.S. (2016). Mechanisms and consequences of doublestrand DNA break formation in chromatin. J. Cell. Physiol. 231, 3– 14. DOI: 10.1002/jcp.25048
• 18.   Chamorro González, R., Conrad, T., Stoeber, M. C., Xu, R., Giurgiu, M., Rodriguez-Fos, E., ... & Henssen, A. G. (2023). Parallel sequencing of extrachromosomal circular DNAs and transcriptomes in single cancer cells. Nature Genetics, 55(5), 880-890.DOI: 10.1038/s41588- 023-01386-y
• 19.   Chang, L., Deng, E., Wang, J., Zhou, W., Ao, J., Liu, R., ... & Fan, X. (2023). Single-cell thirdgeneration sequencing-based multi-omics uncovers gene expression changes governed by ecDNA and structural variants in cancer cells. Clinical and Translational Medicine, 13(8), e1351. DOI: 10.1002/ctm2.1351
• 20.   Chen, C. Y. (2024). Chromothripsis in myeloid malignancies. Annals of Hematology, 103(10),111 IJGMR/Volume 15, Number 2/July–December 2026 Shruthi D. J, Kiran Kumar H. B. An update on chromothripsis: biology, mechanisms and applications 3955-3962. doi: 10.1007/s00277-024-05814-9. Epub 2024 May 30. DOI: 10.1007/s00277-024- 05814-9
• 21.   Chen, X., Agustinus, A. S., Li, J., Dibona, M., & Bakhoum, S. F. (2025). Chromosomal instability as a driver of cancer progression. Nature Reviews Genetics, 26(1), 31-46. DOI: 10.1038/ s41576-024-00761-7
• 22.   Chiang, C., Jacobsen, J. C., Ernst, C., Hanscom, C., Heilbut, A., Blumenthal, I. & Talkowski, M. E. (2012). Complex reorganization and predominant non-homologous repair following chromosomal breakage in karyotypically balanced germline rearrangements and transgenic integration. Nature genetics, 44(4), 390-397. doi: 10.1038/ng.2202.
• 23.   Chowdhry, S., Milutinovic, S., Tse, E., Garcia, S., Perusse, D., Ritland, M., ... & Kasibhatla, S. (2023). Tumors driven by oncogene amplified extrachromosomal DNA (ecDNA) demonstrate enhanced sensitivity to cell cycle checkpoint kinase 1 (CHK1) inhibition. Cancer Research, 83(7_Supplement),1626-1626.
• 24.   Ciccia, A., and Elledge, S.J. (2010). The DNA damage response: making it safe to play with knives. Mol. Cell 40, 179–204. DOI: 10.1016/j. molcel.2010.09.019
• 25.   Cimini, D. (2023). Twenty years of merotelic kinetochore attachments: a historical perspective. Chromosome Research, 31(3), 18. https://doi.org/10.1007/s10577-023-09727-7
• 26.   Clay, D.E., Bretscher, H.S., Jezuit, E.A., et al. (2021). Persistent DNA damage signaling and DNA polymerase theta promote broken chromosome segregation. J. Cell Biol. 220, e202106116. DOI: 10.1083/jcb.202106116
• 27.   Cortés-Ciriano, I., Lee, J. J. K., Xi, R., Jain, D., Jung, Y. L., Yang, L., ... & Park, P. J. (2020). Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing. Nature genetics, 52(3), 331-341. https://doi.org/10.1038/s41588-019-0576-7
• 28.   Crasta, K. (2014). DNA breaks and chromosome pulverisation from errors in mitosis. Mutagenesis, 29(6), 542. DOI: 10.1038/ nature10802
• 29.   Cumbo, C., Tota, G., Anelli, L., Zagaria, A., Specchia, G., & Albano, F. (2020). TP53 in myelodysplastic syndromes: recent biological and clinical findings. International Journal of Molecular Sciences, 21(10), 3432. DOI: 10.3390/ ijms21103432
• 30.   De Marco Zompit, M., Esteban, M. T., Mooser, C., Adam, S., Rossi, S. E., Jeanrenaud, A., ... & Stucki, M. (2022). The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis. Nature communications, 13(1), 4143. https://doi.org/10.1038/s41467-022-31865-5
• 31.   Decarvalho, A. C., Kim, H., Poisson, L. M., Winn, M. E., Mueller, C., Cherba, D., ... & Verhaak, R. G. (2018). Discordant inheritance of chromosomal and extrachromosomal DNA elements contributes to dynamic disease evolution in glioblastoma. Nature genetics, 50(5), 708-717. DOI: 10.1038/s41588- 018-0105-0
• 32.   Deshpande, V., Luebeck, J., Nguyen, N. P. D., Bakhtiari, M., Turner, K. M., Schwab, R., ... & Bafna, V. (2019). Exploring the landscape of focal amplifications in cancer using AmpliconArchitect. Nature communications, 10(1), 392. DOI: 10.1038/ s41467-018-08200-y
• 33.   Devillers, R., Dos Santos, A., Destombes, Q., Laplante, M., & Elowe, S. (2024). Recent insights into the causes and consequences of chromosome mis-segregation. Oncogene, 43(43), 3139-3150. https://doi.org/10.1038/s41388-024-03163-5.
• 34.   Dewhurst, S. M., Yao, X., Rosiene, J., Tian, H., Behr, J., Bosco, N., ... & Imieliński, M. (2021). Structural variant evolution after telomere crisis. Nature communications, 12(1), 2093. DOI: 10.1038/s41467-021-21933-7
• 35.   Drews, R. M., Hernando, B., Tarabichi, M., Haase, K., Lesluyes, T., Smith, P. S., ... & Markowetz, F. (2022). A pan-cancer compendium of chromosomal instability. Nature, 606(7916), 976-983. DOI: 10.1038/s41586-022-04789-9
• 36.   Duan, H., Peng, X., Qin, S. et al. Micronuclei: origins, assays, mechanisms, diseases and treatments. Sig Transduct Target Ther 11, 114 (2026). https://doi.org/10.1038/s41392-025- 02538-8
• 37.   Dufton, M., & Bouzayen, R. (2021). Complex reciprocal translocations, more complex than initially thought: a case report. F&S Reports, 2(4), 487-492. DOI: 10.1016/j.xfre.2021.08.003
• 38.   Fenech, M., Knasmueller, S., Knudsen, L. E., Kirsch-Volders, M., Deo, P., Franzke, B., ... & Bonassi, S. (2021). “Micronuclei and Disease” special issue: Aims, scope, and synthesis of outcomes. Mutation Research/Reviews in Mutation Research, 788, 108384. DOI: 10.1016/j. mrrev.2021.108384 39. Fukami, M., Shima, H., Suzuki, E., Ogata, T., Matsubara, K., & Kamimaki, T. (2017). Catastrophic cellular events leading to complex chromosomal rearrangements in112 Indian Journal of Genetics and Molecular Research IJGMR/Volume 15, Number 2/July–December 2026 the germline. Clinical genetics, 91(5), 653-660. DOI: 10.1111/cge.12928
• 40.   Gao, S., Wang, S., Zhao, Z., Zhang, C., Liu, Z., Ye, P., ... & Wang, L. (2022). TUBB4A interacts with MYH9 to protect the nucleus during cell migration and promotes prostate cancer via GSK3β/β-catenin signalling. Nature communications, 13(1), 2792. DOI: 10.1038/ s41467-022-30409-1
• 41.   Gerstung, M., Jolly, C., Leshchiner, I., Dentro, S. C., Gonzalez, S., Rosebrock, D., ... & Van Loo, P. (2020). The evolutionary history of 2,658 cancers. Nature, 578(7793), 122-128. https:// doi.org/10.1038/s41586-019-1907-7
• 42.   Giurgiu, M., Wittstruck, N., Rodriguez-Fos, E., Chamorro González, R., Brückner, L., Krienelke-Szymansky, A., ... & Henssen, A. G. (2024). Reconstructing extrachromosomal DNA structural heterogeneity from longread sequencing data using Decoil. Genome research, 34(9), 1355-1364. DOI: 10.1101/ gr.279123.124
• 43.   Gridina M and Fishman V (2022). Multilevel view on chromatin architecture alterations in cancer. Front. Genet. 13:1059617. doi: 10.3389/ fgene.2022.1059617
• 44.   Gröbner, S. N., Worst, B. C., Weischenfeldt, J., Buchhalter, I., Kleinheinz, K., Rudneva, V. A., & Pfister, S. M. (2018). The landscape of genomic alterations across childhood cancers. Nature, 555(7696),321-327. DOI: 10.1038/nature25480
• 45.   Groelly, F. J., Fawkes, M., Dagg, R. A., Blackford, A. N., & Tarsounas, M. (2023). Targeting DNA damage response pathways in cancer. Nature Reviews Cancer, 23(2), 78-94. DOI: 10.1038/s41568-022-00535-5
• 46.   Hanahan, D. (2022). Hallmarks of cancer: new dimensions. Cancer discovery, 12(1), 31-46. https://doi.org/10.1158/2159-8290.CD-21- 1059
• 47.   Harding, S. M., Benci, J. L., Irianto, J., Discher, D. E., Minn, A. J., & Greenberg, R. A. (2017). Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature, 548(7668), 466-470. DOI: 10.1038/nature23470
• 48.   Hastings, R. J., Moore, S., & Chia, N. (Eds.). (2024). ISCN 2024: an international System for human cytogenomic nomenclature (2024). Karger Medical and Scientific Publishers. doi: 10.1159/000549238.
• 49.   Hatch, E. M., Fischer, A. H., Deerinck, T. J., & Hetzer, M. W. (2013). Catastrophic nuclear envelope collapse in cancer cell micronuclei. Cell, 154(1), 47-60. DOI: 10.1016/j. cell.2013.06.007 50. Helleday, T. (2013). Putting poly (ADP-ribose) polymerase and other DNA repair inhibitors into clinical practice. Current Opinion in Oncology, 25(6), 609-614. DOI: 10.1097/ CCO.0000000000000016
• 51.   Hong, C., Schubert, M., Tijhuis, A. E., Requesens, M., Roorda, M., van den Brink, A., & Foijer, F. (2022). cGAS–STING drives the IL-6-dependent survival of chromosomally instable cancers. Nature, 607(7918), 366- 373. DOI: 10.1038/s41586-022-04847-2
• 52.   Horak, P., Heining, C., Kreutzfeldt, S., Hutter, B., Mock, A., Hüllein, J., ... & Frohling, S. (2021). Comprehensive genomic and transcriptomic analysis for guiding therapeutic decisions in patients with rare cancers. Cancer discovery, 11(11), 2780-2795.DOI: 10.1158/2159- 8290.CD-21-0126
• 53.   Hosea, R., Hillary, S., Naqvi, S., Wu, S., & Kasim, V. (2024). The two sides of chromosomal instability: drivers and brakes in cancer. Signal transduction and targeted therapy, 9(1), 75. https://doi.org/10.1038/s41392-024-01767-7
• 54.   Huang, Y., Lin, L., Liu, X., et al. (2019). BubR1 phosphorylates CENP-E as a switch enabling the transition from lateral association to endon capture of spindle microtubules. Cell Res. 29, 562–578. DOI: 10.1038/s41422-019-0178-z
• 55.   Hung, K. L., Luebeck, J., Dehkordi, S. R., Colón, C. I., Li, R., Wong, I. T. L., ... & Chang, H. Y. (2022). Targeted profiling of human extrachromosomal DNA by CRISPRCATCH. Nature genetics, 54(11), 1746-1754. DOI: 10.1038/s41588-022-01190-0
• 56.   Jiang, H., & Chan, Y. W. (2024). Chromatin bridges: stochastic breakage or regulated resolution?. Trends in Genetics, 40(1), 69-82. https://doi.org/10.1016/j.tig.2023.10.004.
• 57.   Jiang, M., Chen, P., Wang, L., Li, W., Chen, B., Liu, Y., ... & Zhou, C. (2020). cGASSTING, an important pathway in cancer immunotherapy. Journal of hematology & oncology, 13(1),81.DOI: 10.1186/s13045-020- 00916-z
• 58.   Kats, I., Schreiber, H. S., Simovic, M., Sant, P., Mallm, J. P., Li, A., ... & Ernst, A. (2023). Spatial and temporal transcriptomics of SHH-medulloblastoma with chromothripsis identifies multiple genetic clones that resist to treatment and lead to relapse. bioRxiv, 2023-03. DOI: 10.3390/cancers13123056
• 59.   Kaufman, B., Shapira-Frommer, R., Schmutzler, R. K., Audeh, M. W., Friedlander, M., Balmaña,113 IJGMR/Volume 15, Number 2/July–December 2026 Shruthi D. J, Kiran Kumar H. B. An update on chromothripsis: biology, mechanisms and applications J., ... & Domchek, S. M. (2015). Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. Journal of clinical oncology, 33(3), 244-250. DOI: 10.1200/ JCO.2014.56.2728
• 60.   Klaasen, S. J., Truong, M. A., van Jaarsveld, R. H., Koprivec, I., Štimac, V., de Vries, S. G., ... & Kops, G. J. (2022). Nuclear chromosome locations dictate segregation error frequencies. Nature, 607(7919), 604-609. DOI: 10.1038/s41586-022-04938-0
• 61.   Kloosterman, W. P., Hoogstraat, M., Paling, O., Tavakoli-Yaraki, M., Renkens, I., Vermaat, J. S., & Cuppen, E. (2011). Chromothripsis is a common mechanism driving genomic rearrangements in primary and metastatic colorectal cancer. Genome biology, 12(10)R103. DOI: 10.1186/gb-2011-12-10-r103
• 62.   Kloosterman, W. P., Tavakoli-Yaraki, M., van Roosmalen, M. J., van Binsbergen, E., Renkens, I., Duran, K., & Cuppen, E. (2012). Constitutional chromothripsis rearrangements involve clustered double-stranded DNA breaks and nonhomologous repair mechanisms. Cell reports, 1(6), 648-655. DOI: 10.1016/j. celrep.2012.05.009
• 63.   Koche, R. P., Rodriguez-Fos, E., Helmsauer, K., Burkert, M., MacArthur, I. C., Maag, J., ... & Henssen, A. G. (2020). Extrachromosomal circular DNA drives oncogenic genome remodeling in neuroblastoma. Nature genetics, 52(1), 29-34. DOI: 10.1038/s41588-019- 0547-z
• 64.   Kolb, T., Khalid, U., Simović, M., Ratnaparkhe, M., Wong, J., Jauch, A., ... & Ernst, A. (2021). A versatile system to introduce clusters of genomic double-strand breaks in large cell populations. Genes, Chromosomes and Cancer, 60(5), 303-313. DOI: 10.1002/gcc.22890
• 65.   Koltsova, A. S., Pendina, A. A., Efimova, O. A., Chiryaeva, O. G., Kuznetzova, T. V., & Baranov, V. S. (2019). On the complexity of mechanisms and consequences of chromothripsis: an update. Frontiers in genetics, 10, 393. DOI: 10.3389/fgene.2019.00393
• 66.   Koltsova, A. S., Pendina, A. A., Efimova, O. A., Chiryaeva, O. G., Kuznetzova, T. V., & Baranov, V. S. (2019). On the complexity of mechanisms and consequences of chromothripsis: an update. DOI: 10.3389/fgene.2019.00393
• 67.   Korbel, J. O., & Campbell, P. J. (2013). Criteria for inference of chromothripsis in cancer genomes. Cell, 152(6), 1226-1236. DOI: 10.1016/j.cell.2013.02.023
• 68.   Kouznetsova, A., Kitajima, T. S., Brismar, H., & Höög, C. (2019). Post-metaphase correction of aberrant kinetochore-microtubule attachments in mammalian eggs. The EMBO Reports, 20(8), EMBR201947905. https://doi.org/10.15252/ embr.201947905.
• 69.   Krupina, K., Goginashvili, A., and Cleveland, D.W. (2023). Scrambling the genome in cancer: causes and consequences of complex chromosome rearrangements. Nat. Rev. Genet. 25, 196–210.DOI: 10.1038/s41576-023-00663-0
• 70.   Kumar, S., Yadav, P., Maurya, A., Yadav, S. C., & Prasad, T. (2026). Molecular Pathogenesis of HPV16-Associated Cervical Cancer: From Viral Entry to Therapeutic Interventions. Chemistry Select, 11(1),e05590.
• 71.   Laine, A., Nagelli, S.G., Farrington, C., et al. (2021). CIP2A Interacts with TopBP1 and drives basal-like breast cancer tumorigenesis. Cancer Res. 81, 4319–4331. DOI: 10.1158/0008- 5472.CAN-20-3651
• 72.   Lange, J. T., Rose, J. C., Chen, C. Y., Pichugin, Y., Xie, L., Tang, J., ... & Mischel, P. S. (2022). The evolutionary dynamics of extrachromosomal DNA in human cancers. Nature genetics, 54(10),1527-1533. DOI: 10.1038/s41588-022-01177-x 73. Lee, J. J. K., Jung, Y. L., Cheong, T. C., Espejo Valle-Inclan, J., Chu, C., Gulhan, D. C., ... & Park, P. J. (2023). ERα-associated translocations underlie oncogene amplifications in breast cancer. Nature, 618(7967),1024-1032. doi:10.1038/s41586-023-06057-w.
• 74.   Leimbacher, P.A., Jones, S.E., Shorrocks, A.K., et al. (2019). MDC1 Interacts with TOPBP1 to maintain chromosomal stability during mitosis. Mol. Cell 74, 571–583.e8. DOI: 10.1016/j. molcel.2019.02.014
• 75.   Li, F., Ming, W., Lu, W., Wang, Y., Li, X., Dong, X., & Bai, Y. (2023). FLED: a full-length eccDNA detector for long-reads sequencing data. Briefings in Bioinformatics, 24(6), bbad388. DOI: 10.1093/bib/bbad388
• 76.   Li, M. M., Ewton, A. A., & Smith, J. L. (2013). Using cytogenetic rearrangements for cancer prognosis and treatment (pharmacogenetics). Current Genetic Medicine Reports, 1(2), 99-112.https://doi.org/10.1007/ s40142-013-0011-9
• 77.   Li, Y., Roberts, N. D., Wala, J. A., Shapira, O., Schumacher, S. E., Kumar, K. & Campbell, P. J. (2020). Patterns of somatic structural variation in human cancer genomes. Nature, 578(7793),114 Indian Journal of Genetics and Molecular Research IJGMR/Volume 15, Number 2/July–December 2026 112-121.DOI: 10.1038/s41586-019-1913-9
• 78.   Li, Y., Schwab, C., Ryan, S. L., Papaemmanuil, E., Robinson, H. M., Jacobs, P., ... & Harrison, C. J. (2014). Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblasticleukaemia. Nature, 508(7494),98- 102.DOI: 10.1038/nature13115
• 79.   Liddiard, K., Ruis, B., Takasugi, T., Harvey, A., Ashelford, K. E., Hendrickson, E. A., & Baird, D. M. (2016). Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4. Genome Research, 26(5), 588-600. doi: 10.1101/gr.200840.115.
• 80.   Lim, J., Rodriguez, R., Williams, K., Silva, J., Gutierrez, A. G., Tyler, P., ... & Heger, K. (2024). The exonuclease TREX1 constitutes an innate immune checkpoint limiting cGAS/ STING-mediated antitumor immunity. Cancer Immunology Research, 12(6), 663-672. DOI: 10.1158/2326-6066.CIR-23-1078
• 81.   Lima, I., Borges, F., Pombinho, A., & Chavarria, D. (2025). The spindle assembly checkpoint: Molecular mechanisms and kinase-targeted drug discovery. Drug Discovery Today, 30(5), 104355. ,https://doi.org/10.1016/j. drudis.2025.104355.
• 82.   Lin, Y. F., Hu, Q., Mazzagatti, A., Valle-Inclán, J. E., Maurais, E. G., Dahiya, R., ... & Ly, P. (2023). Mitotic clustering of pulverized chromosomes from micronuclei. Nature, 618(7967), 1041- 1048. DOI: 10.1038/s41586-023-05974-0
• 83.   Liu, X., Wang, H., Dou, Z., et al. (2020). Phase separation drives decision making in cell division. J. Biol. Chem. 295, 13419–13431. DOI: 10.1074/jbc.REV120.011746
• 84.   Ly, P., Brunner, S. F., Shoshani, O., Kim, D. H., Lan, W., Pyntikova, T., ... & Cleveland, D. W. (2019). Chromosome segregation errors generate a diverse spectrum of simple and complex genomic rearrangements. Nature genetics, 51(4), 705-715. DOI: 10.1038/s41588- 019-0360-8
• 85.   Ly, P., Teitz, L. S., Kim, D. H., Shoshani, O., Skaletsky, H., Fachinetti, D., ... & Cleveland, D. W. (2017). Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining. Nature cell biology, 19(1), 68- 75. DOI: 10.1038/ncb3450
• 86.   Ly, P., Teitz, L. S., Kim, D. H., Shoshani, O., Skaletsky, H., Fachinetti, D., ... & Cleveland, D. W. (2017). Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining. Nature cell biology, 19(1), 68-75. DOI: 10.1038/ncb3450
• 87.   MacDonald, K. M., Nicholson-Puthenveedu, S., Tageldein, M. M., Khasnis, S., Arrowsmith, C. H., & Harding, S. M. (2023). Antecedent chromatin organization determines cGAS recruitment to ruptured micronuclei. Nature Communications, 14(1), 556. DOI: 10.1038/ s41467-023-36195-8 88. Maciejowski, J., and de Lange, T. (2017). Telomeres in cancer: tumour suppression and genome instability. Nat. Rev. Mol. Cell Biol. 18, 175–186. DOI: 10.1038/nrm.2016.171
• 89.   Maciejowski, J., Chatzipli, A., Dananberg, A., Chu, K., Toufektchan, E., Klimczak, L. J., ... & de Lange, T. (2020). APOBEC3-dependent kataegis and TREX1-driven chromothripsis during telomere crisis. Nature genetics, 52(9), 884-890. DOI: 10.1038/s41588-020-0667-5
• 90.   Maciejowski, J., Li, Y., Bosco, N., Campbell, P. J., & De Lange, T. (2015). Chromothripsis and kataegis induced by telomere crisis. Cell, 163(7), 1641-1654. DOI: 10.1016/j.cell.2015.11.054
• 91.   Maiato, H., & Silva, S. (2023). Double-checking chromosome segregation. Journal of Cell Biology, 222(5), e202301106. doi: 10.1083/ jcb.202301106. Epub 2023 Apr 5. DOI: 10.1083/ jcb.202301106
• 92.   Maiato, H., & Silva, S. (2023). Double-checking chromosome segregation. Journal of Cell Biology, 222(5),e202301106.doi: https://doi. org/10.1083/jcb.202301106
• 93.   Mammel, A. E., Huang, H. Z., Gunn, A. L., Choo, E., & Hatch, E. M. (2022). Chromosome length and gene density contribute to micronuclear membrane stability. Life science alliance, 5(2).DOI: 10.26508/lsa.202101210
• 94.   Mardin, B. R., Drainas, A. P., Waszak, S. M., Weischenfeldt, J., Isokane, M., Stütz, A. M., ... & Korbel, J. O. (2015). A cell-based model system links chromothripsis with hyperploidy. Molecular systems biology, 11(9), MSB156505. DOI: 10.15252/msb.20156505
• 95.   Mazzagatti, A., Engel, J. L., & Ly, P. (2024). Boveri and beyond: Chromothripsis and genomic instability from mitotic errors. Molecular cell, 84(1), 55-69. DOI: 10.1016/j. molcel.2023.11.002
• 96.   Mc Gee, M. M. (2015). Targeting the mitotic catastrophe signaling pathway in cancer.Mediators of inflammation,2015(1),146282. DOI: 10.1155/2015/146282115 IJGMR/Volume 15, Number 2/July–December 2026 Shruthi D. J, Kiran Kumar H. B. An update on chromothripsis: biology, mechanisms and applications
• 97.   McAinsh, A.D., and Kops, G.J.P.L. (2023). Principles and dynamics of spindle assembly checkpoint signalling. Nat. Rev. Mol. Cell Biol. 24, 543–559. DOI: 10.1038/s41580-023-00593-z
• 98.   McAinsh, A.D., and Kops, G.J.P.L. (2023). Principles and dynamics of spindle assembly checkpoint signalling. Nat. Rev. Mol. Cell Biol. 24, 543–559. DOI: 10.1038/s41580-023-00593-z
• 99.   Mohr, L., Toufektchan, E., von Morgen, P., Chu, K., Kapoor, A., & Maciejowski, J. (2021). ER-directed TREX1 limits cGAS activation at micronuclei. Molecular cell, 81(4),724-738. DOI: 10.1016/j.molcel.2020.12.037
• 100.   Molenaar, J. J., Koster, J., Zwijnenburg, D. A., Van Sluis, P., Valentijn, L. J., Van Der Ploeg, I., ... & Versteeg, R. (2012). Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature, 483(7391), 589-593. DOI: 10.1038/ nature10910
• 101.   Molenaar, J. J., Koster, J., Zwijnenburg, D. A., Van Sluis, P., Valentijn, L. J., Van Der Ploeg, I., ... & Versteeg, R. (2012). Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature, 483(7391), 589-593. DOI: 10.1038/ nature10910
• 102.   Molenaar, J. J., Koster, J., Zwijnenburg, D. A., Van Sluis, P., Valentijn, L. J., Van Der Ploeg, I., ... & Versteeg, R. (2012). Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature, 483(7391), 589-593. DOI: 10.1038/ nature10910
• 103.   Møller, H. D. et al. CRISPR-C: circularization of genes and chromosome by CRISPR in human cells. Nucleic Acids Res. 46, e131 (2018). DOI: 10.1093/nar/gky767
• 104.   Nagelli, S., & Westermarck, J. (2024). CIP2A coordinates phosphosignaling, mitosis, and the DNA damage response. Trends in cancer, 10(1), 52-64. DOI: 10.1016/j.trecan.2023.09.001
• 105.   Nazaryan, L., Stefanou, E. G., Hansen, C., Kosyakova, N., Bak, M., Sharkey, F. H., ... & Tommerup, N. (2014). The strength of combined cytogenetic and matepair sequencing techniques illustrated by a germline chromothripsis rearrangement involving FOXP2. European Journal of Human Genetics, 22(3), 338-343. doi: 10.1038/ ejhg.2013.147.
• 106.   Nazaryan-Petersen, L., and Tommerup, N. (2016). Chromothripsis and human genetic disease. In: eLS. John Wiley& Sons, Ltd, https://doi.org/10.1002/9780470015902. a0024627.
• 107.   Ngo, G. H., Cleal, K., Seifan, S., Miklos, V., Barwacz, S. A., Ruis, B. L., ... & Baird, D. M. (2026). Mitotic microhomologymediated break-induced replication promotes chromoanasynthesis. NatureCommunications, 17(1),3375.https://doi. org/10.1038/s41467-026-70086-y
• 108.   Niederhuber, James O. Armitage, Michael B. Kastan, James H. Doroshow, Joel E. Tepper,Abeloff’s Clinical Oncology (Sixth Edition),Elsevier,2020,Pages 56-73.e5,ISBN 9780323476744,https://doi.org/10.1016/B978- 0-323-47674-4.00004-9.
• 109.   Onoja, A. O., Nwani, C. D., Alimba, C. G., Olasoji, O. O., Obarombi, G. T., & Shaibu, E. L. (2026). Micronuclei formation: small nuclear packages with big genomic consequences. The Nucleus, 69(1), 205-225.https://doi. org/10.1007/s13237-025-00542-5.
• 110.   Pappas, G., Munk, S. H. N., Watanabe, K., Thomas, Q., Gal, Z., Gram, H. H., ... & Bartek, J. (2023). MDC1 maintains active elongation complexes of RNA polymerase II. Cell reports, 42(1). doi: 10.1016/j.celrep.2022.111979. Epub 2023 Jan 12.
• 111.   Pellestor, F., Gaillard, J. B., Schneider, A., Puechberty, J., & Gatinois, V. (2022, March). Chromoanagenesis, the mechanisms of a genomic chaos. In Seminars in Cell & Developmental Biology (Vol. 123, pp. 90-99). Academic Press.,https://doi.org/10.1016/j. semcdb.2021.01.004.
• 112.   Pellestor, F., Ganne, B., & Gatinois, V. (2025). Chromothripsis. Chromoanagenesis: Methods and Protocols, 3-33.doi: 10.1007/978-1-0716- 4750-9_1. DOI: 10.1007/978-1-0716-4750-9_1
• 113.   Petsalaki, E., and Zachos, G. (2020). DNA damage response proteins regulating mitotic cell division: double agents preserving genome stability. FEBS J. 287, 1700–1721. DOI: 10.1111/ febs.15240
• 114.   Philippos, G. (2025). Investigating the mechanistic basis of chromothripsis initiation and the clonal evolution of chromothriptic cells (Doctoral dissertation).
• 115.   Pleuger, R., & Westermann, S. (2026). Mitotic error correction and the spindle assembly checkpoint: a tension-filled relationship. Cell Cycle, 25(1), 1–19. https://doi.org/10.1080/15 384101.2026.2653527116 Indian Journal of Genetics and Molecular Research IJGMR/Volume 15, Number 2/July–December 2026
• 116.   Poot, M. (2018). Genes, proteins, and biological pathways preventing chromothripsis. Methods Mol. Biol. 1769, 231–251. DOI: 10.1007/978-1- 4939-7780-2_15
• 117.   Pradella, D., Zhang, M., Gao, R., Yao, M. A., Gluchowska, K. M., Florez, Y. C., ... & Ventura, A. (2023). Immortalization and transformation of primary cells mediated by engineered ecDNAs. bioRxiv,2023-06.https:// doi.org/10.1101/2023.06.25.546239
• 118.   Qin, H., Tang, D., Li, Z., Yang, F., Wang, J., Liu, X., ... & Gao, W. (2026). SLC4A7 Drives NSCLC Progression and Immune Evasion via pH Dysregulation: Its Targeting Synergizes with Anti-PD-1/L1 Therapy. International Journal of Biological Sciences, 22(8), 3950. doi:10.7150/ ijbs.129129
• 119.   Rahal, Z., Scheet, P., & Kadara, H. (2024). Somatic mutations in normal tissues: calm before the storm. Cancer discovery, 14(4), 605- 609. doi: 10.1158/2159-8290.CD-23-1508.
• 120.   Ramanjulu, J. M., Pesiridis, G. S., Yang, J., Concha, N., Singhaus, R., Zhang, S. Y., & Bertin, J. (2018). Design of amidobenzimidazole STING receptor agonists with systemic activity. Nature, 564(7736),439-443. DOI: 10.1038/s41586-018-0705-y
• 121.   Ratnaparkhe, M., Wong, J. K., Wei, P. C., Hlevnjak, M., Kolb, T., Simovic, M., ... & Ernst, A. (2018). Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors. Nature communications, 9(1), 4760. DOI: 10.1038/ s41467-018-06925-4
• 122.   Rausch, T., Jones, D. T., Zapatka, M., Stütz, A. M., Zichner, T., Weischenfeldt, J., ... & Korbel, J. O. (2012). Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell, 148(1), 59-71. DOI: 10.1016/j. cell.2011.12.013
• 123.   Rausch, T., Snajder, R., Leger, A., Simovic, M., Giurgiu, M., Villacorta, L., ... & Korbel, J. O. (2023). Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures. Cell Genomics, 3(4). DOI: 10.1016/j. xgen.2023.100281
• 124.   Rosswog, C., Bartenhagen, C., Welte, A., Kahlert, Y., Hemstedt, N., Lorenz, W., ... & Fischer, M. (2021). Chromothripsis followed by circular recombination drives oncogene amplification in human cancer. Nature genetics, 53(12), 1673-1685. DOI: 10.1038/ s41588-021-00951-7
• 125.   Rothkamm, K., & Lloyd, D. (2014). Established and emerging methods of biological dosimetry. Comprehensive biomedical physics, 289-310.https://doi.org/10.1016/B978-0-444- 53632-7.00814-5.
• 126.   Sato, Y., & Hayashi, M. T. (2024). Micronucleus is not a potent inducer of the cGAS/STING pathway. Life science alliance, 7(4). DOI: 10.26508/lsa.202302424
• 127.   Sekelsky, J. (2017). DNA repair in drosophila: mutagens, models, and missing genes. Genetics 205, 471–490. DOI: 10.1534/genetics.116.186759
• 128.   Shi, M., Patti, G. J., Gunter, M. J., Govindan, R., Lansdorp-Vogelaar, I., Wang, T., ... & Cao, Y. (2026). Accelerating discovery of cancer causes for prevention in the era of risingearlyonsetcancers. Cell, 189(8),2232-2253. ,https:// doi.org/10.1016/j.cell.2026.03.019
• 129.   Shoshani, O., Brunner, S. F., Yaeger, R., Ly, P., Nechemia-Arbely, Y., Kim, D. H., ... & Cleveland, D. W. (2021). Chromothripsis drives the evolution of gene amplification in cancer. Nature, 591(7848), 137-141. DOI: 10.1038/s41586-020-03064-z
• 130.   Shoshani, O., Brunner, S. F., Yaeger, R., Ly, P., Nechemia-Arbely, Y., Kim, D. H., ... & Cleveland, D. W. (2021). Chromothripsis drives the evolution of gene amplification in cancer. Nature, 591(7848), 137-141. DOI: 10.1038/s41586-020-03064-z
• 131.   Simovic, M., Bolkestein, M., Moustafa, M., Wong, J. K., Körber, V., Benedetto, S., ... & Ernst, A. (2021). Carbon ion radiotherapy eradicates medulloblastomas with chromothripsis in an orthotopic Li-Fraumeni patient-derived mouse model. Neuro-oncology, 23(12),2028-2041. DOI: 10.1093/neuonc/noab127
• 132.   Srikar Nagelli, Jukka Westermarck,CIP2A coordinates phosphosignaling, mitosis, and the DNA damage response,Trends in Cancer,Volume 10, Issue 1,2024,Pages 52- 64,ISSN 2405-8033,https://doi.org/10.1016/j. trecan.2023.09.001.
• 133.   Steele, C. D., Abbasi, A., Islam, S. A., Bowes, A. L., Khandekar, A., Haase, K., ... & Pillay, N. (2022). Signatures of copy number alterations in human cancer. Nature, 606(7916),984-991. DOI: 10.1038/s41586-022-04738-6
• 134.   Stephens, P. J., Greenman, C. D., Fu, B., Yang, F., Bignell, G. R., Mudie, L. J., ... & Campbell, P. J. (2011). Massive genomic rearrangement acquired in a single catastrophic event117 IJGMR/Volume 15, Number 2/July–December 2026 Shruthi D. J, Kiran Kumar H. B. An update on chromothripsis: biology, mechanisms and applications during cancerdevelopment. cell, 144(1),27-40. DOI: 10.1016/j.cell.2010.11.055
• 135.   Takaki, T., Millar, R., Hiley, C. T., & Boulton, S. J. (2024). Micronuclei induced by radiation, replication stress, or chromosome segregation errors do not activate cGASSTING. Molecularcell, 84(11),2203-2213. DOI: 10.1038/nature23470
• 136.   Tang, S., Stokasimov, E., Cui, Y., & Pellman, D. (2022). Breakage of cytoplasmic chromosomes by pathological DNA base excision repair. Nature, 606(7916), 930-936. DOI: 10.1038/s41586-022-04767-1
• 137.   Tani, T., Mathsyaraja, H., Campisi, M., Li, Z. H., Haratani, K., Fahey, C. G., ... & Barbie, D. A. (2024). TREX1 inactivation unleashes cancer cell STING–interferon signaling and promotes antitumor immunity. Cancer discovery, 14(5), 752-765. DOI: 10.1158/2159-8290.CD-23-0700
• 138.   Taylor, A. M. R. (2001). Chromosome instability syndromes. Best Practice & Research Clinical Haematology, 14(3), 631-644. DOI: 10.1053/ beha.2001.0158
• 139.   Teles Alves, I., Hiltemann, S., Hartjes, T., van der Spek, P., Stubbs, A., Trapman, J., & Jenster, G. (2013). Gene fusions by chromothripsis of chromosome 5q in the VCaP prostate cancer cell line. Human genetics, 132(6), 709-713. DOI: 10.1007/s00439-013-1308-1
• 140.   Toufektchan, E., Dananberg, A., Striepen, J., Hickling, J. H., Shim, A., Chen, Y., ... & Maciejowski, J. (2024). Intratumoral TREX1 induction promotes immune evasion by limiting type I IFN. Cancer Immunology Research, 12(6), 673-686. DOI: 10.1158/2326- 6066.CIR-23-1093
• 141.   Trivedi, P., Steele, C. D., Au, F. K., Alexandrov, L. B., & Cleveland, D. W. (2023). Mitotic tethering enables inheritance of shattered micronuclear chromosomes. Nature, 618(7967), 1049-1056. DOI: 10.1038/s41586-023-06216-z
• 142.   Umbreit, N. T., Zhang, C. Z., Lynch, L. D., Blaine, L. J., Cheng, A. M., Tourdot, R., ... & Pellman, D. (2020). Mechanisms generating cancer genome complexity from a single cell division error. Science, 368(6488), eaba0712. DOI: 10.1126/science.aba0712
• 143.   Vargas-Rondón, N., Villegas, V. E., & RondónLagos, M. (2018). The Role of Chromosomal Instability in Cancer and Therapeutic Responses. Cancers, 10(1), 4. https://doi. org/10.3390/cancers10010004
• 144.   Vitale, I., Galluzzi, L., Castedo, M., & Kroemer, G. (2011). Mitotic catastrophe: a mechanism for avoiding genomic instability. Nature reviews Molecular cell biology, 12(6), 385- 392. DOI: 10.1038/nrm3115
• 145.   Voronina, N., Wong, J. K., Hubschmann, D., Hlevnjak, M., Uhrig, S., Heilig, C. E., ... & Ernst, A. (2020). The landscape of chromothripsis across adult cancer types. Nature communications, 11(1),2320.https://doi. org/10.1038/s41467-020-16134-7
• 146.   Voronina, N., Wong, J. K., Hubschmann, D., Hlevnjak, M., Uhrig, S., Heilig, C. E., ... & Ernst, A. (2020). The landscape of chromothripsis across adult cancer types. Nature communications, 11(1),2320.DOI: 10.1038/ s41467-020-16134-7
• 147.   Warecki, B., Bast, I., Tajima, M., & Sullivan, W. (2023). Connections between sister and nonsister telomeres of segregating chromatids maintain euploidy. Current Biology, 33(1), 58- 74. DOI: 10.1016/j.cub.2022.11.038
• 148.   Waszak, S. M., Northcott, P. A., Buchhalter, I., Robinson, G. W., Sutter, C., Groebner, S., ... & Pfister, S. M. (2018). Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. The Lancet Oncology, 19(6),785-798. DOI: 10.1016/S1470- 2045(18)30242-0
• 149.   Wu, T., Wu, C., Zhao, X., Wang, G., Ning, W., Tao, Z., ... & Liu, X. S. (2022). Extrachromosomal DNA formation enables tumor immune escape potentially through regulating antigen presentation gene expression. Scientific reports, 12(1), 3590. DOI: 10.1038/s41598-022- 07530-8 150. Xu, K., Ding, L., Chang, T. C., Shao, Y., Chiang, J., Mulder, H., ... & Wu, G. (2019). Structure and evolution of double minutes in diagnosis and relapse brain tumors. Acta neuropathologica, 137(1), 123-137. DOI: 10.1007/ s00401-018-1912-1
• 151.   Yam CQX, Lim HH and Surana U (2022). DNA damage checkpoint execution and the rules of its disengagement. Front. Cell Dev. Biol. 10:1020643. doi: 10.3389/fcell.2022.1020643.
• 152.   Yatskevich, S., Kroonen, J. S., Alfieri, C., Tischer, T., Howes, A. C., Clijsters, L., ... & Barford, D. (2021). Molecular mechanisms of APC/C release from spindle assembly checkpoint inhibition by APC/C SUMOylation. Cell reports, 34(13).https://doi.org/10.1016/j. celrep.2021.108929.
• 153.   Yi, E., Chamorro González, R., Henssen, A. G., & Verhaak, R. G. (2022). Extrachromosomal 118. DNA amplifications in cancer. Nature Reviews Genetics, 23(12), 760-771.DOI: 10.1038/s41576-
• 154.   Zhang, C. Z., Leibowitz, M. L., & Pellman, D. (2013). Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements. Genes & development, 27(23),2513-2530.DOI: 10.1101/ gad.229559.113
• 155.   Zhang, C. Z., Mendez-Dorantes, C., Burns, K. H., & Pellman, D. (2026). A breakage– replication/fusion process explains complex rearrangements and segmental DNA amplification. Nature Genetics, 1-12. https:// doi.org/10.1038/s41588-025-02434-5
• 156.   Zhang, C. Z., Spektor, A., Cornils, H., Francis, J. M., Jackson, E. K., Liu, S., ... & Pellman, D. (2015). Chromothripsis from DNA damage in micronuclei. Nature, 522(7555), 179-184. DOI: 10.1038/nature14493
• 157.   Zhang, C.-Z., Spektor, A., Cornils, H., et al. (2015). Chromothripsis from DNA damage in micronuclei. Nature 522, 179–184. DOI: 10.1038/nature14493
• 158.   Zhang, R., & Bozic, I. (2024). Accumulation of oncogenic mutations during progression from healthy tissue to cancer. Bulletin of Mathematical Biology, 86(12), 142. https://doi.org/10.1007/ s11538-024-01372-3
• 159.   Zhang, S., Xiao, X., Yi, Y., Wang, X., Zhu, L., Shen, Y., ... & Wu, C. (2024). Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets. Signal transduction and targeted therapy, 9(1), 149. https://doi.org/10.1038/s41392-024-01848-7.
• 160.   Zhu, Y., Gujar, A. D., Wong, C. H., Tjong, H., Ngan, C. Y., Gong, L., ... & Wei, C. L. (2021). Oncogenic extrachromosomal DNA functions as mobile enhancers to globally amplify chromosomal transcription. Cancer cell, 39(5), 694-707. DOI: 10.1016/j.ccell.2021.03.006

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