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The Generation, Detection, and Prevention of Genomic Instability During Cancer Progression and Metastasis

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Genomic Instability and Cancer Metastasis

Part of the book series: Cancer Metastasis - Biology and Treatment ((CMBT,volume 20))

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Abstract

Genome stability is tightly regulated through the cell cycle. Aberrations in genome structure and sequence are a hallmark of malignancy and these changes can allow abnormal cells to escape the regulatory mechanisms that would otherwise direct these cells into apoptosis or senescence. When genome instability occurs, it can happen as large or small structural changes in the genome, changes in gene expression, or even changes at the epigenetic level. There are many environmental factors that can induce DNA damage and strain the machinery that is responsible for maintaining genome stability. In some cases, such as UV light or chemical carcinogens, it is possible to avoid these factors and thus reduce the risk of cancer. But, in other instances, hereditary mutations impair the function of genes and their products, which normally protect the stability of the genome. While genomic instability offers selective advantages to the tumor, the tumor-specific loss of these pathways may provide therapeutic opportunities, which could be personalized through knowledge of the specific types of genomic instability that characterize an individual’s tumor.

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Abbreviations

BER:

Base excision repair

BFB:

Break fusion break

CDK:

Cyclin dependent kinase

CGH:

Comparative genomic hybridization

CIN:

Chromosome instability

CpG:

C-phosphate-G

CRC:

Colorectal cancer

DDR:

DNA damage response

DNA:

Deoxynucleic acid

DSB:

Double strand break

EMT:

Epithelial to mesenchymal transition

HDR:

Homology directed repair

LOH:

Loss of heterozygosity

MET:

Mesenchymal to epithelial transition

MIN or MSI,:

Microsatellite instability

MMR:

Mismatch repair

mtDNA:

Mitochondrial DNA

NER:

Nucleotide excision repair

NHEJ:

Non-homologous end joining

NIN:

Nucleotide instability

PCR:

Polymerase chain reaction

SAC:

Spindle assembly checkpoint

UV:

Ultraviolet

References

  1. Futreal PA et al (2004) A census of human cancer genes. Nat Rev. Cancer 4:177–183

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Hardy PA, Zacharias H (2005) Reappraisal of the Hansemann-Boveri hypothesis on the origin of tumors. Cell Biol Int 29:983–992

    PubMed  Google Scholar 

  3. Boveri T (1914) Zur Frage der Entstehung Maligner Tumoren. Gustav Fischer Verlag, Jena

    Google Scholar 

  4. Nowell P, Hungerford D (1960) Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst 25:85–109

    CAS  PubMed  Google Scholar 

  5. Miki Y et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71

    CAS  PubMed  Google Scholar 

  6. Futreal PA et al (1994) BRCA1 mutations in primary breast and ovarian carcinomas. Science 266:120–122

    Google Scholar 

  7. Korkola J, Gray JW (2010) Breast cancer genomes–form and function. Curr Opin Genet Dev 20:4–14

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Lengauer C, Kinzler KW, Vogelstein B (1998) Genetic instabilities in human cancers. Nature 396:643–649

    CAS  PubMed  Google Scholar 

  9. Almoguera C et al (1988) Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53:549–554

    CAS  PubMed  Google Scholar 

  10. Lee H-C et al (2005) Mitochondrial genome instability and mtDNA depletion in human cancers. Ann N Y Acad Sci 1042:109–122

    CAS  PubMed  Google Scholar 

  11. Pikor L et al (2013) The detection and implication of genome instability in cancer. Cancer Metastasis Rev 32:341–352

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Risinger JI et al (1993) Genetic instability of microsatellites in endometrial carcinoma. Cancer Res 53:5100–5103

    CAS  PubMed  Google Scholar 

  13. Leach FS et al (1993) Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75:1215–1225

    CAS  PubMed  Google Scholar 

  14. Rhyu MG, Park WS, Meltzer SJ (1994) Microsatellite instability occurs frequently in human gastric carcinoma. Oncogene 9:29–32

    CAS  PubMed  Google Scholar 

  15. Fishel R et al (1994) The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 77:1027–1038

    Google Scholar 

  16. Kim W et al (1999) Microsatellite instability (MSI) in non-small cell lung cancer (NSCLC) is highly associated with transforming growth factor-beta type II receptor (TGF-beta RII) frameshift. Anticancer Res 20:1499–1502

    Google Scholar 

  17. Halling KC et al (1999) Origin of microsatellite instability in gastric cancer. Am J Pathol 155:205–211

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Boland CR, Goel A (2010) Microsatellite instability in colorectal cancer. Gastroenterology 138:2073–2087

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Gagos S, Irminger-Finger I (2005) Chromosome instability in neoplasia: chaotic roots to continuous growth. Int J Biochem Cell Biol 37:1014–1033

    CAS  PubMed  Google Scholar 

  20. Wang SI et al (1997) Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res 57:4183–4186

    CAS  PubMed  Google Scholar 

  21. Jefford CE, Irminger-Finger I (2006) Mechanisms of chromosome instability in cancers. Critical Rev Oncol/Hematol 59:1–14

    Google Scholar 

  22. Moyzis RK et al (1988) A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc Natl Acad Sci U S A 85:6622–6626

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Meyne J, Ratliff RL, Moyzis RK (1989) Conservation of the human telomere sequence (TTAGGG)n among vertebrates. Proc Natl Acad Sci U S A 86:7049–7053

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Bailey SM, Murnane JP (2006) Telomeres, chromosome instability and cancer. Nucleic Acids Res 34:2408–2417

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Chakhparonian M, Wellinger RJ (2003) Telomere maintenance and DNA replication: how closely are these two connected? Trends Genet 19:439–446

    CAS  PubMed  Google Scholar 

  26. Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345:458–460

    CAS  PubMed  Google Scholar 

  27. Kondo S et al (1998) Antisense telomerase treatment: induction of two distinct pathways, apoptosis and differentiation. FASEB J 12:801–811

    CAS  PubMed  Google Scholar 

  28. Zhang X et al (1999) Telomere shortening and apoptosis in telomerase-inhibited human tumor cells. Genes Dev 13:2388–2399

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Hahn WC et al (1999) Inhibition of telomerase limits the growth of human cancer cells. Nat Med 5:1164–1170

    CAS  PubMed  Google Scholar 

  30. De Lange T (2005) Telomere-related genome instability in cancer. Cold Spring Harb Symp Quant Biol 70:197–204

    CAS  PubMed  Google Scholar 

  31. Riha K, Heacock ML, Shippen DE (2006) The role of the nonhomologous end-joining DNA double-strand break repair pathway in telomere biology. Annu Rev Genet 40:237–277

    CAS  PubMed  Google Scholar 

  32. Maser RS, DePinho RA (2002) Connecting chromosomes, crisis, and cancer. Science 297:565–569

    CAS  PubMed  Google Scholar 

  33. Feldser DM, Hackett JA, and CW (2003) Greider, telomere dysfunction and the initiation of genome instability. Nat Rev Cancer 3:623–627

    CAS  PubMed  Google Scholar 

  34. Rudolph KL et al (1999) Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96:701–712

    CAS  PubMed  Google Scholar 

  35. Kim NW et al (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266:2011–2015

    CAS  PubMed  Google Scholar 

  36. Sharma S, Kelly TK, Jones PA (2010) Epigenetics in cancer. Carcinog 31:27–36

    CAS  Google Scholar 

  37. Sarkies P, Sale JE (2012) Cellular epigenetic stability and cancer. Trends Genet 28:118–127

    CAS  PubMed  Google Scholar 

  38. Miller OJ et al (1974) 5-Methylcytosine localised in mammalian constitutive heterochromatin. Nature 251:636–637

    CAS  PubMed  Google Scholar 

  39. Wilson AS, Power BE, Molloy PL (2007) DNA hypomethylation and human diseases. Biochim Biophys Acta 1775:138–162

    CAS  PubMed  Google Scholar 

  40. Sperandeo M et al (2000) Relaxation of insulin-like growth factor 2 imprinting and discordant methylation at KvDMR1 in two first cousins affected by Beckwith-Wiedemann and Klippel-Trenaunay-Weber syndromes. Am J Hum Genet 66:841–847

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128:683–692

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428

    CAS  PubMed  Google Scholar 

  43. Ehrlich M (2002) DNA methylation in cancer: too much, but also too little. Oncogene 21:5400–5413

    CAS  PubMed  Google Scholar 

  44. Jones PA, Laird PW (1999) Cancer epigenetics comes of age. Nat Genet 21:163–167

    CAS  PubMed  Google Scholar 

  45. Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705

    CAS  PubMed  Google Scholar 

  46. Fraga MF et al (2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37:391–400

    CAS  PubMed  Google Scholar 

  47. Seligson DB et al (2005) Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435:1262–1266

    CAS  PubMed  Google Scholar 

  48. Seligson DB et al (2009) Global levels of histone modifications predict prognosis in different cancers. Am J Pathol 174:1619–1628

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Schneider A-C et al (2011) Global histone H4K20 trimethylation predicts cancer-specific survival in patients with muscle-invasive bladder cancer. BJU Int 108:E290–E296

    PubMed  Google Scholar 

  50. Ellinger J et al (2010) Global levels of histone modifications predict prostate cancer recurrence. Prostate 70:61–69

    CAS  PubMed  Google Scholar 

  51. Kurdistani SK (2011) Histone modifications in cancer biology and prognosis. Prog Drug Res 67:91–106

    CAS  PubMed  Google Scholar 

  52. Osada H et al (2004) Reduced expression of class II histone deacetylase genes is associated with poor prognosis in lung cancer patients. Int J Cancer.112:26–32

    CAS  PubMed  Google Scholar 

  53. Mavrich TN et al (2008) A barrier nucleosome model for statistical positioning of nucleosomes throughout the yeast genome. Genome Res 18:1073–1083

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Lin JC et al (2007) Role of nucleosomal occupancy in the epigenetic silencing of the MLH1 CpG island. Cancer Cell 12:432–444

    CAS  PubMed  Google Scholar 

  55. Hatziapostolou M, Iliopoulos D (2011) Epigenetic aberrations during oncogenesis. Cell Mol Life Sci 68:1681–1702

    CAS  PubMed  Google Scholar 

  56. You JS, Jones PA (2012) Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell 22:9–20

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Barretina J et al (2012) The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483:603–607

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Matei DE, Nephew KP (2010) Epigenetic therapies for chemoresensitization of epithelial ovarian cancer. Gynecol Oncolo 116:195–201

    CAS  Google Scholar 

  59. Juergens RA et al (2011) Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov 1:598–607

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Stoeber K et al (2001) DNA replication licensing and human cell proliferation. J Cell Sci 114:2027–2041

    CAS  PubMed  Google Scholar 

  61. Nishitani H, Lygerou Z (2002) Control of DNA replication licensing in a cell cycle. Genes Cells 7:523–534

    CAS  PubMed  Google Scholar 

  62. Aguilera A, García-Muse T (2013) Causes of genome instability. Annu Rev Genet 47:1–32

    CAS  PubMed  Google Scholar 

  63. Shen Z (2011) Genomic instability and cancer: an introduction. J M Cell Biol 3:1–3

    CAS  Google Scholar 

  64. Doxsey S (2001) Re-evaluating centrosome function. Nat Rev Mol Cell Biol 2:688–698

    CAS  PubMed  Google Scholar 

  65. Nigg EA, Stearns T (2011) The centrosome cycle: Centriole biogenesis, duplication and inherent asymmetries. Nat Cell Biol 13:1154–1160

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Heald R et al (1996) Self-organization of microtubules into bipolar spindles around artificial chromosomes in Xenopus egg extracts. Nature 382:420–425

    CAS  PubMed  Google Scholar 

  67. Nigg EA, Centrosome A (2002) Cause of consequence of cancer progression? Nat Rev Genet 3:815–815

    Google Scholar 

  68. Ko MA et al (2005) Plk4 haploinsufficiency causes mitotic infidelity and carcinogenesis. Nat Genet 37:883–888

    CAS  PubMed  Google Scholar 

  69. Fukasawa K (2005) Centrosome amplification, chromosome instability and cancer development. Cancer Lett 230:6–19

    CAS  PubMed  Google Scholar 

  70. Pellegrino R et al (2010) Oncogenic and tumor suppressive roles of polo-like kinases in human hepatocellular carcinoma. Hepatology 51:857–868

    CAS  PubMed  Google Scholar 

  71. Khodjakov A et al (2002) De novo formation of centrosomes in vertebrate cells arrested during S phase. J Cell Biol 158:1171–1181

    CAS  PubMed Central  PubMed  Google Scholar 

  72. La Terra S et al (2005) The de novo centriole assembly pathway in HeLa cells: cell cycle progression and centriole assembly/maturation. J Cell Biol 168:713–722

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Peel N et al (2007) Overexpressing centriole-replication proteins in vivo induces centriole overduplication and de novo formation. Curr Biol 17:834–843

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Merdes A et al (1996) A complex of NuMA and cytoplasmic dynein is essential for mitotic spindle assembly. Cell 87:447–458

    CAS  PubMed  Google Scholar 

  75. Maxwell CA et al (2003) RHAMM is a centrosomal protein that interacts with dynein and maintains spindle pole stability. Mol Biol Cell 14:2262–2276

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Maxwell CA et al (2005) Receptor for hyaluronan-mediated motility correlates with centrosome abnormalities in multiple myeloma and maintains mitotic integrity. Cancer Res 65:850–860

    CAS  PubMed  Google Scholar 

  77. Luca MD, Lavia P, Guarguaglini G (2006) A functional interplay between Aurora-A, Plk1 and TPX2 at spindle poles. Cell Cycle 5:296–303

    Google Scholar 

  78. Haren L et al (2009) NuMA is required for proper spindle assembly and chromosome alignment in prometaphase. BMC Res Notes 2:64

    PubMed Central  PubMed  Google Scholar 

  79. Silk AD, Holland AJ, Cleveland DW (2009) Requirements for NuMA in maintenance and establishment of mammalian spindle poles. J Cell Biol 184:677–690

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Hut HMJ et al (2003) Centrosomes split in the presence of impaired DNA integrity during mitosis. Mol Biol Cell 14:1993–2004

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Krämer A, Maier B, Bartek J (2011) Centrosome clustering and chromosomal (in)stability: a matter of life and death. Mol Oncol 5:324–335

    PubMed  Google Scholar 

  82. Quintyne NJ et al (2005) Spindle multipolarity is prevented by centrosomal clustering. Science 307:127–129

    CAS  PubMed  Google Scholar 

  83. Marthiens V, Piel M, Basto R (2012) Never tear us apart–the importance of centrosome clustering. J Cell Sci 125:3281–3292

    CAS  PubMed  Google Scholar 

  84. Ogden A, Rida PC, Aneja R (2012) Let’s huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy. Cell Death Differ 19:1255–1267

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Weaver BA et al (2007) Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell 11:25–36

    CAS  PubMed  Google Scholar 

  86. Birkbak NJ et al (2011) Paradoxical relationship between chromosomal instability and survival outcome in cancer. Cancer Res 71:3447–3452

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Gergely F, Basto R (2008) Multiple centrosomes: together they stand, divided they fall. Genes Dev 22:2291–2296

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Dechant R, Glotzer M (2003) Centrosome separation and central spindle assembly act in redundant pathways that regulate microtubule density and trigger cleavage furrow formation. Dev Cell 4:333–344

    CAS  PubMed  Google Scholar 

  89. Bringmann H et al (2007) LET-99, GOA-1/GPA-16, and GPR-1/2 are required for aster-positioned cytokinesis. Curr Biol 17:185–191

    CAS  PubMed  Google Scholar 

  90. Bird AW, Hyman AA (2008) Building a spindle of the correct length in human cells requires the interaction between TPX2 and Aurora A. J Cell Biol 182:289–300

    CAS  PubMed Central  PubMed  Google Scholar 

  91. von Dassow G et al (2009) Action at a distance during cytokinesis. J Cell Biol 187:831–845

    Google Scholar 

  92. Dunsch AK et al (2012) Dynein light chain 1 and a spindle-associated adaptor promote dynein asymmetry and spindle orientation. J Cell Biol 198: 1039–1054

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Cimini D et al (2001) Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells. J Cell Biol 153:517–527

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Cimini D et al (2002) Merotelic kinetochore orientation versus chromosome mono-orientation in the origin of lagging chromosomes in human primary cells. J Cell Sci 115:507–515

    CAS  PubMed  Google Scholar 

  95. Normand G, King R (2010) Understanding cytokinesis failure. Adv Exp Med Biol 676:27–55

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Shackney SE et al (1989) Model for the genetic evolution of human solid tumors. Cancer Res 49:3344–3354

    CAS  PubMed  Google Scholar 

  97. Lanni JS, Jacks T (1998) Characterization of the p53-dependent postmitotic checkpoint following spindle disruption. Mol Cell Biol 18:1055–1064

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Andreassen PR et al (2001) Tetraploid state induces p53-dependent arrest of nontransformed mammalian cells in G1. Mol Biol Cell 12:1315–1328

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Borel F et al (2002) Multiple centrosomes arise from tetraploidy checkpoint failure and mitotic centrosome clusters in p53 and RB pocket protein-compromised cells. Proc Natl Acad Sci U S A 99:9819–9824

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Fujiwara T et al (2005) Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437:1043–1047

    CAS  PubMed  Google Scholar 

  101. McClintock B (1941) The stability of broken ends of chromosomes in Zea Mays. Genetics 26:234–282

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Gisselsson D et al (2000) Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity. Proc Natl Acad Sci U S A 97:5357–5362

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Acilan C, Potter DM, Saunders WS (2007) DNA repair pathways involved in anaphase bridge formation. Genes Chromosomes Cancer 46:522–531

    CAS  PubMed  Google Scholar 

  104. Vogelstein B (1990) Cancer. A deadly inheritance. Nature 348(6303):681–682

    CAS  PubMed  Google Scholar 

  105. Levine DS et al (1991) Formation of the tetraploid intermediate is associated with the development of cells with more than four centrioles in the elastase-simian virus 40 tumor antigen transgenic mouse model of pancreatic cancer. Proc Natl Acad Sci U S A 88:6427–6431

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Galipeau PC et al (1996) 17p (p53) allelic losses, 4N (G2/tetraploid) populations, and progression to aneuploidy in Barrett’s esophagus. Proc Natl Acad Sci U S A 93:7081–7084

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Pihan GA et al (2003) Centrosome abnormalities and chromosome instability occur together in pre-invasive carcinomas. Cancer Res 63:1398–1404

    CAS  PubMed  Google Scholar 

  108. Storchova Z, Pellman D (2004) From polyploidy to aneuploidy, genome instability and cancer. Nat Rev Mol Cell Biol 5:45–54

    CAS  PubMed  Google Scholar 

  109. Olaharski AJ et al (2006) Tetraploidy and chromosomal instability are early events during cervical carcinogenesis. Carcinog 27:337–343

    CAS  Google Scholar 

  110. Maya R et al (2001) ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev 15:1067–1077

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Wahl GM, Carr AM (2001) The evolution of diverse biological responses to DNA damage: insights from yeast and p53. Nat Cell Biol 3:E277–286

    CAS  PubMed  Google Scholar 

  112. Shiloh Y (2003) ATM and related protein kinases: safeguarding genome integrity. Nat Rev. Cancer 3:155–168

    CAS  PubMed  Google Scholar 

  113. Bartek J, Lukas J (2003) Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer cell 3:421–429

    CAS  PubMed  Google Scholar 

  114. Harper JW et al (1993) The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75:805–816

    CAS  PubMed  Google Scholar 

  115. Burns TF, El-Deiry WS (1999) The p53 pathway and apoptosis. J Cell Physiol 181:31–39

    Google Scholar 

  116. Ferbeyre G et al (2002) Oncogenic ras and p53 Cooperate to induce cellular senescence. Mol Cell Biol 22:3497–3508

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Coleman TR, Dunphy WG (1994) Cdc2 regulatory factors. Curr Opin Cell Biol 6:877–882

    CAS  PubMed  Google Scholar 

  118. Jin P, Gu Y, Morgan DO Role of inhibitory CDC2 phosphorylation in radiation-induced G2 arrest in human cells. J Cell Biol 134:963–970

    Google Scholar 

  119. Kommajosyula N, Rhind N (2006) Cdc2 tyrosine phosphorylation is not required for the S-phase DNA damage checkpoint in fission yeast. Cell Cycle 5:2495–24500

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Wilkie AO et al (1990) A truncated human chromosome 16 associated with alpha thalassaemia is stabilized by addition of telomeric repeat (TTAGGG)n. Nature 346:868–871

    CAS  PubMed  Google Scholar 

  121. Maresca TJ, Salmon ED (2010) Welcome to a new kind of tension: translating kinetochore mechanics into a wait-anaphase signal. J Cell Sci 123:825–835

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Lara-Gonzalez P, Westhorpe FG, Taylor SS (2012) The spindle assembly checkpoint. Curr Biol CB 22:R966–980

    CAS  Google Scholar 

  123. Redondo DM, Meraldi P(2011) The spindle assembly checkpoint: Clock or domino? In: Kubiak JZ (ed) Cell cycle in development. Springer Berlin Heidelberg, Berlin, pp 75–91

    Google Scholar 

  124. Lens SM, Voest EE, Medema RH (2010) Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat Rev. Cancer 10:825–841

    CAS  PubMed  Google Scholar 

  125. Foley EA, Kapoor TM (2013) Microtubule attachment and spindle assembly checkpoint signalling at the kinetochore. Nat Rev Mol Cell Biol 14:25–37

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Anand S, Penrhyn-Lowe S, Venkitaraman AR (2003) AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer Cell 3:51–62

    CAS  PubMed  Google Scholar 

  127. Jiang Y et al (2003) AuroraA overexpression overrides the mitotic spindle checkpoint triggered by nocodazole, a microtubule destabilizer. Oncogene 22:8293–8301

    CAS  PubMed  Google Scholar 

  128. Liu D, Davydenko O, Lampson MA (2012) Polo-like kinase-1 regulates kinetochore-microtubule dynamics and spindle checkpoint silencing. J Cell Biol 198:491–499

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Bharadwaj R, Yu H (2004) The spindle checkpoint, aneuploidy, and cancer. Oncogene 23:2016–2027

    CAS  PubMed  Google Scholar 

  130. Lampson MA, Kapoor TM (2005) The human mitotic checkpoint protein BubR1 regulates chromosome-spindle attachments. Nat Cell Biol 7:93–98

    CAS  PubMed  Google Scholar 

  131. Jacquemont S et al (2002) High risk of malignancy in mosaic variegated aneuploidy syndrome. Am J Med Genet 109:17–21

    PubMed  Google Scholar 

  132. Hanks S et al (2006) Comparative genomic hybridization and BUB1B mutation analyses in childhood cancers associated with mosaic variegated aneuploidy syndrome. Cancer Lett 239:234–238

    CAS  PubMed  Google Scholar 

  133. Bohers E et al (2008) Gradual reduction of BUBR1 protein levels results in premature sister-chromatid separation then in aneuploidy. Hum Genet 124:473–478

    CAS  PubMed  Google Scholar 

  134. Karess R, Wassmann K, Rahmani Z (2012) New insights into the role of BubR1 in mitosis and beyond. Int Rev Cell Mol Biol 306:223–273

    Google Scholar 

  135. Hanks S et al (2004) Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat Genet 36:1159–1161

    CAS  PubMed  Google Scholar 

  136. Matsuura S et al (2006) Monoallelic BUB1B mutations and defective mitotic-spindle checkpoint in seven families with premature chromatid separation (PCS) syndrome. Am J Med Genet A 140:358–367

    PubMed  Google Scholar 

  137. Suijkerbuijk SJE et al (2010) Molecular causes for BUBR1 dysfunction in the human cancer predisposition syndrome mosaic variegated aneuploidy. Cancer Res 70:4891–4900

    CAS  PubMed Central  PubMed  Google Scholar 

  138. Clingen PH et al (1995) Correlation of UVC and UVB cytotoxicity with the induction of specific photoproducts in T-lymphocytes and fibroblasts from normal human donors. Photochem Photobiol 61(2):163–170

    CAS  PubMed  Google Scholar 

  139. Jhappan C, Noonan FP, Merlino G (2003) Ultraviolet radiation and cutaneous malignant melanoma. Oncogene 22(20):3099–3112

    CAS  PubMed  Google Scholar 

  140. van der Pols JC et al (2006) prolonged prevention of squamous cell carcinoma of the skin by regular sunscreen use. Cancer Epidemiol Biomark Prev 15:2546–2548

    Google Scholar 

  141. Hecht SS (1999) Tobacco smoke, carcinogens and lung cancer. J Natl Cancer Inst 91:1194–210

    CAS  PubMed  Google Scholar 

  142. Shopland DR (1995) Tobacco use and its contribution to early cancer mortality with a special emphasis on cigarette smoking. Environ Health Perspect 103:131–142

    PubMed Central  PubMed  Google Scholar 

  143. Lowenfels AB, Maisonneuve P (2004) Epidemiology and prevention of pancreatic cancer. Jpn J Clin Oncol 34:238–244

    PubMed  Google Scholar 

  144. Khalade A et al (2010) Exposure to benzene at work and the risk of leukemia: a systematic review and meta-analysis. Environ Health 9:31

    PubMed Central  PubMed  Google Scholar 

  145. Hiraku Y, Kawanishi S (1996) Oxidative DNA damage and apoptosis induced by benzene metabolites. Cancer Res 56:5172–5178

    CAS  PubMed  Google Scholar 

  146. Orjuela M et al (2000) Presence of human papilloma virus in tumor tissue from children with retinoblastoma : an alternative mechanism for tumor development. Clin Cancer Res 6:4010–4016

    CAS  PubMed  Google Scholar 

  147. Hawley-Nelson P et al (1989) HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes. EMBO J 8:3905–3910

    CAS  PubMed Central  PubMed  Google Scholar 

  148. Münger K et al (1989) The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol 63:4417–4421

    PubMed Central  PubMed  Google Scholar 

  149. Halbert CL, Demers GW, Galloway DA (1992) The E6 and E7 genes of human papillomavirus type 6 have weak immortalizing activity in human epithelial cells. J Virol 66:2125–2134

    CAS  PubMed Central  PubMed  Google Scholar 

  150. Hashida T, Yasumoto S (1991) Induction of chromosome abnormalities in mouse and human epidermal keratinocytes by the human papillomavirus type 16 E7 oncogene. J Gen virol 72:1569–1577

    CAS  PubMed  Google Scholar 

  151. White AE, Livanos EM, Tlsty TD (1994) Differential disruption of genomic integrity and cell cycle regulation in normal human fibroblasts by the HPV oncoproteins. Genes Dev 8:666–677

    CAS  PubMed  Google Scholar 

  152. Duensing S, Münger K (2004) Mechanisms of genomic instability in human cancer: insights from studies with human papillomavirus oncoproteins. Int J Cancer 109:157–62

    CAS  PubMed  Google Scholar 

  153. Muñoz N et al (2003) Epidemiologic classification of human papillomavirus types associated with cervical cancer. New Engl J Med 348:518–27

    PubMed  Google Scholar 

  154. Blount BC et al (1997) Folate deficiency causes uracil misincorporations into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci U S A 94:3290–3295

    CAS  PubMed Central  PubMed  Google Scholar 

  155. Fenech M (2001) The role of folic acid and vitamin B12 in genomic stability of human cells. Mutat Res 475:57–67

    CAS  PubMed  Google Scholar 

  156. Fenech M et al (2005) Low intake of calcium, folate, nicotinic acid, vitamin E, retinol, beta-carotene and high intake of pantothenic acid, biotin and riboflavin are significantly associated with increased genome instability—results from a dietary intake and micronucleus index survey in South Australia. Carcinog 26:991–999

    CAS  Google Scholar 

  157. Satia JA et al (2005) Diet, lifestyle, and genomic instability in the North Carolina Colon Cancer Study. Cancer Epidemiol Biomark Prev 14:429–436

    CAS  Google Scholar 

  158. Beheshti B et al (2001) Evidence of chromosomal instabilityin prostate cancer determined by spectral karyotyping (SKY) and interphase fish analysis. Neoplasia 3:62–69

    CAS  PubMed Central  PubMed  Google Scholar 

  159. Wan TS, Ma ES (2011) Molecular cytogenetics: an indispensable tool for cancer diagnosis. Chang Gung Med J 35:96–110

    Google Scholar 

  160. Pinkel D et al (1998) High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet 20(2):207–211

    CAS  PubMed  Google Scholar 

  161. Ishkanian AS et al (2004) A tiling resolution DNA microarray with complete coverage of the human genome. Nat Genet 36(3):299–303

    CAS  PubMed  Google Scholar 

  162. Zietkiewicz E, Rafalski A, Labuda D (1994) Genome fingerprinting by simple sequence repeat (SSR)-anchored polymerase chain reaction amplification. Genomics 20:176–183

    CAS  PubMed  Google Scholar 

  163. Stoler DL et al (1999) The onset and extent of genomic instability in sporadic colorectal tumor progression. Proc Natl Acad Sci U S A 96:15121–15126

    CAS  PubMed Central  PubMed  Google Scholar 

  164. Basik M et al (1997) Genomic instability in sporadic colorectal cancer quantitated by inter-simple sequence repeat PCR analysis. Genes Chromosomes Cancer 29:19–29

    Google Scholar 

  165. Tang JC et al (2001) Detection of genetic alterations in esophageal squamous cell carcinomas and adjacent normal epithelia by comparative DNA fingerprinting using inter-simple sequence repeat PCR. Clin Cancer Res 7:1539–1545

    CAS  PubMed  Google Scholar 

  166. Stoler DL et al (2002) Genomic instability measurement in the diagnosis of thyroid neoplasms. Head Neck 24:290–295

    PubMed  Google Scholar 

  167. Samuelsson JK et al (2010) DNA fingerprinting techniques for the analysis of genetic and epigenetic alterations in colorectal cancer. Mutat Res 693:61–76

    CAS  PubMed Central  PubMed  Google Scholar 

  168. Achille A et al (1996) Chromosome 7q allelic losses in pancreatic carcinoma. Cancer Res 56:3808–3813

    CAS  PubMed  Google Scholar 

  169. Zhao X et al (2004) An integrated view of copy number and allelic alterations in the cancer genome using single nucleotide polymorphism arrays. Cancer Res 64:3060–3071

    CAS  PubMed  Google Scholar 

  170. Heinrichs S, Look AT (2007) Identification of structural aberrations in cancer by SNP array analysis. Genome Biol 8:219

    PubMed Central  PubMed  Google Scholar 

  171. Mol BM et al (2014) High resolution SNP array profiling identifies variability in retinoblastoma genome stability. Genes Chromosomes Cancer 14:1–14

    Google Scholar 

  172. Wheeler DA et al (2008) The complete genome of an individual by massively parallel DNA sequencing. Nature 452:872–876

    CAS  PubMed  Google Scholar 

  173. Meyerson M, Gabriel S, Gets G (2010) Advances in understanding cancer genomes through second-generation sequencing. Nat Rev Geneti 11:685–696

    CAS  Google Scholar 

  174. Wang L et al (2012) Whole-exome sequencing of human pancreatic cancers and characterization of genomic instability caused by MLH1 haploinsufficiency and complete deficience. Genome Res 22:208–19

    CAS  PubMed Central  PubMed  Google Scholar 

  175. Habermann JK et al (2009) The gene expression signature of genomic instability in breast cancer is an independent predictor of clinical outcome. Int J Cancer 124:1552–1564

    CAS  PubMed Central  PubMed  Google Scholar 

  176. Mettu RKR et al (2010) A 12-gene genomic instability signature predicts clinical outcomes in multiple cancer types. Int J Biol Markers 25:219–228

    PubMed Central  PubMed  Google Scholar 

  177. Carter SL et al (2006) A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet 38:1043–1048

    CAS  PubMed  Google Scholar 

  178. Roylance R, Endesfelder D, Gorman P (2011) Relationship of extreme chromosomal instability with long-term survival in a retrospective analysis of primary breast cancer. Cancer Epid 20:2183–2194

    Google Scholar 

  179. Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev. Cancer 9:265–273

    CAS  PubMed  Google Scholar 

  180. Yilmaz M, Christofori G (2009) EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev 28:15–33

    PubMed  Google Scholar 

  181. Thiery JP et al (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890

    CAS  PubMed  Google Scholar 

  182. Nguyen DX, Massagué J (2007) Genetic determinants of cancer metastasis. Nat Rev Genet 8:341–352

    CAS  PubMed  Google Scholar 

  183. Campbell PJ et al (2010) The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467:1109–1113

    CAS  PubMed Central  PubMed  Google Scholar 

  184. Ni X et al (2013) Reproducible copy number variation patterns among single circulating tumor cells of lung cancer patients. Proc Natl Acad Sci U S A 110:21083–21088

    CAS  PubMed Central  PubMed  Google Scholar 

  185. Merlo LMF et al (2006) Cancer as an evolutionary and ecological process. Nat Rev. Cancer 6:924–935

    CAS  PubMed  Google Scholar 

  186. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    CAS  PubMed  Google Scholar 

  187. Nowell PC (2014) The clonal evolution of tumor cell populations. Acquired genetic lability permits stepwise selection. Soc Invest Dermatol 194:23–28

    Google Scholar 

  188. Vaupel P, Mayer A (2005) Hypoxia and anemia: effects on tumor biology and treatment resistance. Transfus Clini Biol 12:5–10

    Google Scholar 

  189. Paszek MJ et al (2005) Tensional homeostasis and the malignant phenotype. Cancer cell 8:241–254

    CAS  PubMed  Google Scholar 

  190. Hemmer J, Kraft K (2001) Stability of aneuploid clones during oral squamous cell carcinoma metastasis. Anticancer Res 21:1459–1464

    CAS  PubMed  Google Scholar 

  191. Semenza GL (2008) Tumor metabolism: cancer cells give and take lactate. J Clin Invest 118:3835–3837

    CAS  PubMed Central  PubMed  Google Scholar 

  192. Feron O (2009) Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells. Radiother Oncol 92:329–333

    CAS  PubMed  Google Scholar 

  193. Kennedy KM, Dewhirst MW (2010) Tumor metabolism of lactate: the influence and therapeutic potential for MCT and CD147 regulation. Future Oncol 6:127–148

    CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgements

CAM is supported through a CIHR New Investigator Salary award while HC and MC are supported through a Michael Cuccione Foundation for Childhood Cancer Research scholarship and fellowship, respectively.

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Authors and Affiliations

  1. Department of Pediatrics, Child & Family Research Institute, University of British Columbia, Room 3086, 950 W 28th Ave., V5Z 4H4, Vancouver, BC, Canada

    Helen Chen, Christopher Maxwell & Marisa Connell

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  1. Helen Chen
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  2. Christopher Maxwell
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  3. Marisa Connell
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Correspondence to Christopher Maxwell .

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Editors and Affiliations

  1. Child & Family Research Institute, University of British Columbia, Pediatrics, Vancouver, British Columbia, Canada

    Chris Maxwell

  2. Dept of Cellular & Physiological Sciences, University of British Columbia, Dept. of Cellular & Physiological Sciences, Vancouver, British Columbia, Canada

    Cal Roskelley

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Chen, H., Maxwell, C., Connell, M. (2015). The Generation, Detection, and Prevention of Genomic Instability During Cancer Progression and Metastasis. In: Maxwell, C., Roskelley, C. (eds) Genomic Instability and Cancer Metastasis. Cancer Metastasis - Biology and Treatment, vol 20. Springer, Cham. https://doi.org/10.1007/978-3-319-12136-9_2

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