Abstract
The accurate segregation of chromosomes to daughter cells is essential for healthy development to occur. Imbalances in chromosome number have long been associated with cancers amongst other medical disorders. Little is known whether abnormal chromosome numbers are an early contributor to the cancer progression pathway. Centromere DNA and protein defects are known to impact on the fidelity of chromosome segregation in cell and model systems. In this chapter we discuss recent developments in understanding the contribution of centromere abnormalities at the protein and DNA level and their role in cancer in human and mouse systems.
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References
Babu JR, Jeganathan KB, Baker DJ et al (2003) Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation. J Cell Biol 160:341–353. doi:10.1083/jcb.200211048
Baker DJ, Dawlaty MM, Wijshake T et al (2013) Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan. Nat Cell Biol 15:96–102. doi:10.1038/ncb2643
Baker DJ, Jeganathan KB, Cameron JD et al (2004) BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat Genet 36:744–749. doi:10.1038/ng1382
Baker DJ, Jin F, Jeganathan KB, van Deursen JM (2009) Whole chromosome instability caused by Bub1 insufficiency drives tumorigenesis through tumor suppressor gene loss of heterozygosity. Cancer Cell 16:475–486. doi:10.1016/j.ccr.2009.10.023
Beh TT, Kalitsis P (2015) Centromeres in health, disease and evolution. In: Felekkis K, Voskarides K (eds) Genomic elements in health, disease and evolution. Springer, New York, pp 221–245
Boveri T (1914) Zur Frage der Entstehung maligner Tumoren. Gustav Fischer Verlag, Jena
Cahill DP, Lengauer C, Yu J et al (1998) Mutations of mitotic checkpoint genes in human cancers. Nature 392:300–303. doi:10.1038/32688
Callier P, Faivre L, Cusin V et al (2005) Microcephaly is not mandatory for the diagnosis of mosaic variegated aneuploidy syndrome. Am J Med Genet A 137:204–207. doi:10.1002/ajmg.a.30783
Dai W, Wang Q, Liu T et al (2004) Slippage of mitotic arrest and enhanced tumor development in mice with BubR1 haploinsufficiency. Cancer Res 64:440–445
Danielsen HE, Pradhan M, Novelli M (2016) Revisiting tumour aneuploidy—the place of ploidy assessment in the molecular era. Nat Rev Clin Oncol 13:291–304. doi:10.1038/nrclinonc.2015.208
de Voer RM, Geurts van Kessel A, Weren RDA et al (2013) Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are risk factors for colorectal cancer. Gastroenterology 145:544–547. doi:10.1053/j.gastro.2013.06.001
Dewhurst SM, McGranahan N, Burrell RA et al (2014) Tolerance of whole-genome doubling propagates chromosomal instability and accelerates cancer genome evolution. Cancer Discov 4:175–185. doi:10.1158/2159-8290.CD-13-0285
Diaz-Rodríguez E, Sotillo R, Schvartzman J-M, Benezra R (2008) Hec1 overexpression hyperactivates the mitotic checkpoint and induces tumor formation in vivo. Proc Natl Acad Sci U S A 105:16719–16724. doi:10.1073/pnas.0803504105
Dobles M, Liberal V, Scott ML et al (2000) Chromosome missegregation and apoptosis in mice lacking the mitotic checkpoint protein Mad2. Cell 101:635–645
Dürrbaum M, Storchová Z (2016) Effects of aneuploidy on gene expression: implications for cancer. FEBS J 283:791–802. doi:10.1111/febs.13591
Foijer F, Xie SZ, Simon JE et al (2014) Chromosome instability induced by Mps1 and p53 mutation generates aggressive lymphomas exhibiting aneuploidy-induced stress. Proc Natl Acad Sci U S A 111:13427–13432. doi:10.1073/pnas.1400892111
Fukagawa T, Earnshaw WC (2014) The centromere: chromatin foundation for the kinetochore machinery. Dev Cell 30:496–508. doi:10.1016/j.devcel.2014.08.016
Garsed DW, Marshall OJ, Corbin VDA et al (2014) The architecture and evolution of cancer neochromosomes. Cancer Cell 26:653–667. doi:10.1016/j.ccell.2014.09.010
Gartler SM (2006) The chromosome number in humans: a brief history. Nat Rev Genet 7:655–660. doi:10.1038/nrg1917
Gascoigne KE, Cheeseman IM (2013) Induced dicentric chromosome formation promotes genomic rearrangements and tumorigenesis. Chromosome Res 21:407–418. doi:10.1007/s10577-013-9368-6
Gisselsson D, Pettersson L, Höglund M et al (2000) Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity. Proc Natl Acad Sci U S A 97:5357–5362. doi:10.1073/pnas.090013497
González-Loyola A, Fernández-Miranda G, Trakala M et al (2015) Aurora B overexpression causes aneuploidy and p21Cip1 repression during tumor development. Mol Cell Biol 35:3566–3578. doi:10.1128/MCB.01286-14
Gordon DJ, Resio B, Pellman D (2012) Causes and consequences of aneuploidy in cancer. Nat Rev Genet 13:189–203. doi:10.1038/nrg3123
Haferlach C, Alpermann T, Schnittger S et al (2012) Prognostic value of monosomal karyotype in comparison to complex aberrant karyotype in acute myeloid leukemia: a study on 824 cases with aberrant karyotype. Blood 119:2122–2125. doi:10.1182/blood-2011-10-385781
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. doi:10.1016/j.cell.2011.02.013
Hanks S, Coleman K, Reid S et al (2004) Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat Genet 36:1159–1161. doi:10.1038/ng1449
Hanks S, Rahman N (2005) Aneuploidy-cancer predisposition syndromes: a new link between the mitotic spindle checkpoint and cancer. Cell Cycle 4:225–227
Holland AJ, Cleveland DW (2009) Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat Rev Mol Cell Biol 10:478–487. doi:10.1038/nrm2718
Holland AJ, Cleveland DW (2012) Losing balance: The origin and impact of aneuploidy in cancer. EMBO Rep 13:501–514. doi:10.1038/embor.2012.55
Iwanaga Y, Chi Y-H, Miyazato A et al (2007) Heterozygous deletion of mitotic arrest-deficient protein 1 (MAD1) increases the incidence of tumors in mice. Cancer Res 67:160–166. doi:10.1158/0008-5472.CAN-06-3326
Jacobs PA, Browne C, Gregson N et al (1992) Estimates of the frequency of chromosome abnormalities detectable in unselected newborns using moderate levels of banding. J Med Genet 29:103–108
Kalitsis P, Choo KHA (2012) The evolutionary life cycle of the resilient centromere. Chromosoma 121:327–340. doi:10.1007/s00412-012-0369-6
Kalitsis P, Fowler KJ, Griffiths B et al (2005) Increased chromosome instability but not cancer predisposition in haploinsufficient Bub3 mice. Genes Chromosomes Cancer 44:29–36. doi:10.1002/gcc.20215
Li Y, Schwab C, Ryan SL et al (2014) Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia. Nature 508:98–102. doi:10.1038/nature13115
Lo AWI, Sabatier L, Fouladi B et al (2002) DNA amplification by breakage/fusion/bridge cycles initiated by spontaneous telomere loss in a human cancer cell line. Neoplasia 4:531–538. doi:10.1038/sj.neo.7900267
Maciejowski J, Li Y, Bosco N et al (2015) Chromothripsis and kataegis induced by telomere crisis. Cell 163:1641–1654. doi:10.1016/j.cell.2015.11.054
Mackinnon RN, Campbell LJ (2011) The role of dicentric chromosome formation and secondary centromere deletion in the evolution of myeloid malignancy. Genet Res Int 2011:643628. doi:10.4061/2011/643628
Martínez-A C, van Wely KHM (2011) Centromere fission, not telomere erosion, triggers chromosomal instability in human carcinomas. Carcinogenesis 32:796–803. doi:10.1093/carcin/bgr069
McClintock B (1939) The behavior in successive nuclear divisions of a chromosome broken at meiosis. Proc Natl Acad Sci U S A 25:405–416. doi:10.1073/pnas.25.8.405
Michel LS, Liberal V, Chatterjee A et al (2001) MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature 409:355–359. doi:10.1038/35053094
Mitelman F, Johansson B, Mertens F (2017) Mitelman database of chromosome aberrations and gene fusions in cancer. https://cgap.nci.nih.gov/Chromosomes/Mitelman. Accessed 18 Jan 2017
Moorman AV, Enshaei A, Schwab C et al (2014) A novel integrated cytogenetic and genomic classification refines risk stratification in pediatric acute lymphoblastic leukemia. Blood 124:1434–1444. doi:10.1182/blood-2014-03-562918
Nagaoka SI, Hassold TJ, Hunt PA (2012) Human aneuploidy: mechanisms and new insights into an age-old problem. Nat Rev Genet 13:493–504. doi:10.1038/nrg3245
Nowell PC (2007) Discovery of the philadelphia chromosome: a personal perspective. J Clin Invest 117:2033–2035. doi:10.1172/JCI31771
Orr B, Godek KM, Compton D (2015) Aneuploidy. Curr Biol 25:R538–R542. doi:10.1016/j.cub.2015.05.010
Pavelka N, Rancati G, Li R (2010) Dr Jekyll and Mr Hyde: role of aneuploidy in cellular adaptation and cancer. Curr Opin Cell Biol 22:809–815. doi:10.1016/j.ceb.2010.06.003
Ricke RM, Jeganathan KB, van Deursen JM (2011) Bub1 overexpression induces aneuploidy and tumor formation through Aurora B kinase hyperactivation. J Cell Biol 193:1049–1064. doi:10.1083/jcb.201012035
Santaguida S, Amon A (2015) Short- and long-term effects of chromosome mis-segregation and aneuploidy. Nat Rev Mol Cell Biol 16:473–485. doi:10.1038/nrm4025
Sarova I, Brezinova J, Zemanova Z et al (2016) Molecular cytogenetic analysis of dicentric chromosomes in acute myeloid leukemia. Leuk Res 43:51–57. doi:10.1016/j.leukres.2016.01.001
Schliekelman M, Cowley DO, O’Quinn R et al (2009) Impaired Bub1 function in vivo compromises tension-dependent checkpoint function leading to aneuploidy and tumorigenesis. Cancer Res 69:45–54. doi:10.1158/0008-5472.CAN-07-6330
Silk AD, Zasadil LM, Holland AJ et al (2013) Chromosome missegregation rate predicts whether aneuploidy will promote or suppress tumors. Proc Natl Acad Sci U S A 110:E4134–E4141. doi:10.1073/pnas.1317042110
Slifer EH (1934) Insect development VI. The behavior of grasshopper embryos in anisotonic, balanced salt solutions. J Exp Zool 67:137–157. doi:10.1002/jez.1400670107
Song Q, Merajver SD, Li JZ (2015) Cancer classification in the genomic era: five contemporary problems. Hum Genomics 9:27. doi:10.1186/s40246-015-0049-8
Sotillo R, Hernando E, Díaz-Rodríguez E et al (2007) Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 11:9–23. doi:10.1016/j.ccr.2006.10.019
Stephens PJ, Greenman CD, Fu B et al (2011) Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144:27–40. doi:10.1016/j.cell.2010.11.055
Thiru P, Kern DM, McKinley KL et al (2014) Kinetochore genes are coordinately up-regulated in human tumors as part of a FoxM1-related cell division program. Mol Biol Cell 25:1983–1994. doi:10.1091/mbc.E14-03-0837
Thompson SL, Compton DA (2011) Chromosomes and cancer cells. Chromosome Res Int J Mol Supramol Evol Asp Chromosome Biol 19:433–444. doi:10.1007/s10577-010-9179-y
Tjio JH, Levan A (1956) The chromosome number of man. Hereditas 42:U1–U6
Torres EM, Dephoure N, Panneerselvam A et al (2010) Identification of aneuploidy-tolerating mutations. Cell 143:71–83. doi:10.1016/j.cell.2010.08.038
Valcárcel D, Ademà V, Solé F et al (2013) Complex, not monosomal, karyotype is the cytogenetic marker of poorest prognosis in patients with primary myelodysplastic syndrome. J Clin Oncol Off J Am Soc Clin Oncol 31:916–922. doi:10.1200/JCO.2012.41.6073
Weaver BAA, Silk AD, Montagna C et al (2007) Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell 11:25–36. doi:10.1016/j.ccr.2006.12.003
Wijshake T, Malureanu LA, Baker DJ et al (2012) Reduced life- and healthspan in mice carrying a mono-allelic BubR1 MVA mutation. PLoS Genet 8:e1003138. doi:10.1371/journal.pgen.1003138
Zhang W, Mao J-H, Zhu W et al (2016) Centromere and kinetochore gene misexpression predicts cancer patient survival and response to radiotherapy and chemotherapy. Nat Commun 7:12619. doi:10.1038/ncomms12619
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Beh, T.T., Kalitsis, P. (2017). The Role of Centromere Defects in Cancer. In: Black, B. (eds) Centromeres and Kinetochores. Progress in Molecular and Subcellular Biology, vol 56. Springer, Cham. https://doi.org/10.1007/978-3-319-58592-5_22
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