Cancer and Metastasis Reviews

, Volume 32, Issue 3–4, pp 391–402 | Cite as

Chromosomal instability and transcriptome dynamics in cancer

  • Joshua B. Stevens
  • Steven D. Horne
  • Batoul Y. Abdallah
  • Christine J. Ye
  • Henry H. Heng


Whole transcriptome profiling has long been proposed as a method of identifying cancer-specific gene expression profiles. Indeed, a multitude of these studies have generated vast amounts of expression data for many types of cancer, and most have identified specific gene signatures associated with a given cancer. These studies however, often contradict with each other, and gene lists only rarely overlap, challenging clinical application of cancer gene signatures. To understand this issue, the biological basis of transcriptome dynamics needs to be addressed. Chromosome instability (CIN) is the main contributor to genome heterogeneity and system dynamics, therefore the relationship between CIN, genome heterogeneity, and transcriptome dynamics has important implications for cancer research. In this review, we discuss CIN and its effects on the transcriptome during cancer progression, specifically how stochastic chromosome change results in transcriptome dynamics. This discussion is further applied to metastasis and drug resistance both of which have been linked to multiple diverse molecular mechanisms but are in fact driven by CIN. The diverse molecular mechanisms that drive each process are linked to karyotypic heterogeneity through the evolutionary mechanism of cancer. Karyotypic change and the resultant transcriptome change alter network function within cells increasing the evolutionary potential of the tumor. Future studies must embrace this instability-induced heterogeneity in order to devise new research and treatment modalities that focus on the evolutionary process of cancer rather than the individual genes that are uniquely changed in each tumor. Care is also needed in evaluating results from experimental systems which measure average values of a population.


Genomic instability Karyotypic heterogeneity Transcriptome Genome chaos Punctuated phase of cancer evolution Nonclonal chromosome aberration NCCA Clonal chromosome aberration CCA Network dynamics 



This manuscript is part of a series of studies entitled “The mechanism of somatic and organismal evolution.” This work was partially supported by grants to HHQH from the Komen Foundation, SeeDNA Inc., the National CFIDS Foundation, the Nancy Taylor Foundation for Chronic Diseases, and the US Department of Defense (GW093028). JBS was supported by a WSU CMMG post-doctoral fellowship.


  1. 1.
    Alizadeh, A. A., Eisen, M. B., Davis, R. E., Ma, C., Lossos, I. S., et al. (2000). Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature, 403, 503–511.PubMedCrossRefGoogle Scholar
  2. 2.
    Perou, C. M., Sorlie, T., Eisen, M. B., van de Rijn, M., Jeffrey, S. S., et al. (2000). Molecular portraits of human breast tumours. Nature, 406, 747–752.PubMedCrossRefGoogle Scholar
  3. 3.
    Rimm, D. L. (2000). Molecular biology in cytopathology: current applications and future directions. Cancer, 90, 1–9.PubMedCrossRefGoogle Scholar
  4. 4.
    van't Veer, L. J., Dai, H. Y., van de Vijver, M. J., He, Y. D. D., Hart, A. A. M., et al. (2002). Gene expression profiling predicts clinical outcome of breast cancer. Nature, 415, 530–536.CrossRefGoogle Scholar
  5. 5.
    Buyse, M., Loi, S., van't Veer, L., Viale, G., Delorenzi, M., et al. (2006). Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Nat Cancer Inst, 98, 1183–1192.PubMedCrossRefGoogle Scholar
  6. 6.
    Lehmann, T., & Wrzesinski, T. (2012). The molecular basis of adrenocortical cancer. Cancer Genet, 205, 131–137.PubMedCrossRefGoogle Scholar
  7. 7.
    Lucas, S. M., & Heath, E. I. (2012). Current challenges in development of differentially expressed and prognostic prostate cancer biomarkers. Prostate Cancer, 2012, 640968.PubMedCrossRefGoogle Scholar
  8. 8.
    Simon, R., Radmacher, M. D., Dobbin, K., & McShane, L. M. (2003). Pitfalls in the use of DNA microarray data for diagnostic and prognostic classification. Journal of the National Cancer Institute, 95, 14–18.PubMedCrossRefGoogle Scholar
  9. 9.
    Ein-Dor, L., Zuk, O., & Domany, E. (2006). Thousands of samples are needed to generate a robust gene list for predicting outcome in cancer. Proceedings of the National Academy of Sciences of the United States of America, 103, 5923–5928.PubMedCrossRefGoogle Scholar
  10. 10.
    Venet, D., Dumont, J. E., & Detours, V. (2011). Most random gene expression signatures are significantly associated with breast cancer outcome. PLoS Computational Biology, 7, e1002240.PubMedCrossRefGoogle Scholar
  11. 11.
    Kitano, H. (2002). Systems biology: a brief overview. Science, 295, 1662–1664.PubMedCrossRefGoogle Scholar
  12. 12.
    Cancer Genome Atlas Research Network (2012) Comprehensive genomic characterization of squamous cell lung cancers. Nature 489: 519–525.Google Scholar
  13. 13.
    Brock, A., Chang, H., & Huang, S. (2009). Non-genetic heterogeneity—a mutation-independent driving force for the somatic evolution of tumours. Nature Reviews Genetics, 10, 336–342.PubMedCrossRefGoogle Scholar
  14. 14.
    Yurov, Y. B., Iourov, I. Y., Monakhov, V. V., Soloviev, I. V., Vostrikov, V. M., et al. (2005). The variation of aneuploidy frequency in the developing and adult human brain revealed by an interphase FISH study. Journal of Histochemistry and Cytochemistry, 53, 385–390.PubMedCrossRefGoogle Scholar
  15. 15.
    Heng, H. H. (2013). Biocomplexity: challenging reductionism. In J. P. Sturmberg & C. C. Martin (Eds.), Handbook on systems and complexity in health. London: Springer.Google Scholar
  16. 16.
    Duncan, A. W., Hanlon Newell, A. E., Smith, L., Wilson, E. M., Olson, S. B., et al. (2012). Frequent aneuploidy among normal human hepatocytes. Gastroenterology, 142, 25–28.PubMedCrossRefGoogle Scholar
  17. 17.
    Rehen, S. K., Yung, Y. C., McCreight, M. P., Kaushal, D., Yang, A. H., et al. (2005). Constitutional aneuploidy in the normal human brain. Journal Neurosci, 25, 2176–2180.CrossRefGoogle Scholar
  18. 18.
    Iourov, I. Y., Vorsanova, S. G., & Yurov, Y. B. (2008). Chromosomal mosaicism goes global. Molecular Cytogen, 1, 26.CrossRefGoogle Scholar
  19. 19.
    Stevens, J.B., Abdallah, B.Y., Horne, S.D., Liu, G., Bremer, S.W., et al. (2011). Genetic and epigenetic heterogeneity in cancer. encyclopedia of life sciences. New York: WileyGoogle Scholar
  20. 20.
    Heng, H. H., Stevens, J. B., Bremer, S. W., Liu, G., Abdallah, B. Y., et al. (2011). Evolutionary mechanisms and diversity in cancer. Advances in Cancer Research, 112, 217–253.PubMedCrossRefGoogle Scholar
  21. 21.
    Heng, H. H., Liu, G., Stevens, J. B., Bremer, S. W., Ye, K. J., et al. (2010). Genetic and epigenetic heterogeneity in cancer: the ultimate challenge for drug therapy. Current Drug Targets, 11, 1304–1316.PubMedCrossRefGoogle Scholar
  22. 22.
    Bielas, J. H., & Loeb, L. A. (2005). Quantification of random genomic mutations. Nature Methods, 2, 285–290.PubMedCrossRefGoogle Scholar
  23. 23.
    Gao, C., Furge, K., Koeman, J., Dykema, K., Su, Y., et al. (2007). Chromosome instability, chromosome transcriptome, and clonal evolution of tumor cell populations. Proceedings of the National Academy of Sciences of the United States of America, 104, 8995–9000.PubMedCrossRefGoogle Scholar
  24. 24.
    Tsafrir, D., Bacolod, M., Selvanayagam, Z., Tsafrir, I., Shia, J., et al. (2006). Relationship of gene expression and chromosomal abnormalities in colorectal cancer. Cancer Research, 66, 2129–2137.PubMedCrossRefGoogle Scholar
  25. 25.
    Cheng, L., Wang, P., Yang, S., Yang, Y., Zhang, Q., et al. (2012). Identification of genes with a correlation between copy number and expression in gastric cancer. BMC Medical Genomics, 5, 14.PubMedCrossRefGoogle Scholar
  26. 26.
    Heng, H. H., Liu, G., Stevens, J. B., Bremer, S. W., Ye, K. J., et al. (2011). Decoding the genome beyond sequencing: the new phase of genomic research. Genomics, 98, 242–252.PubMedCrossRefGoogle Scholar
  27. 27.
    Heng, H. H., Stevens, J. B., Liu, G., Bremer, S. W., Ye, K. J., et al. (2006). Stochastic cancer progression driven by non-clonal chromosome aberrations. Journal of Cellular Physiology, 208, 461–472.PubMedCrossRefGoogle Scholar
  28. 28.
    Heng, H. H., Bremer, S. W., Stevens, J., Ye, K. J., Miller, F., et al. (2006). Cancer progression by non-clonal chromosome aberrations. Journal of Cellular Biochemistry, 98, 1424–1435.PubMedCrossRefGoogle Scholar
  29. 29.
    Creekmore, A. L., Silkworth, W. T., Cimini, D., Jensen, R. V., Roberts, P. C., et al. (2011). Changes in gene expression and cellular architecture in an ovarian cancer progression model. PloS One, 6, e17676.PubMedCrossRefGoogle Scholar
  30. 30.
    Lawrenson, L. (2010). Tracking profiles of genomic instability in spontaneous transformation and tumorigenesis. Detroit: Wayne State University School of Medicine.Google Scholar
  31. 31.
    Okamura, K., Feuk, L., Marques-Bonet, T., Navarro, A., & Scherer, S. W. (2006). Frequent appearance of novel protein-coding sequences by frameshift translation. Genomics, 88, 690–697.PubMedCrossRefGoogle Scholar
  32. 32.
    Nicke, B., Bastien, J., Khanna, S. J., Warne, P. H., Cowling, V., et al. (2005). Involvement of MINK, a Ste20 family kinase, in Ras oncogene-induced growth arrest in human ovarian surface epithelial cells. Molecular Cell, 20, 673–685.PubMedCrossRefGoogle Scholar
  33. 33.
    Roberts, P. C., Mottillo, E. P., Baxa, A. C., Heng, H. H., Doyon-Reale, N., et al. (2005). Sequential molecular and cellular events during neoplastic progression: a mouse syngeneic ovarian cancer model. Neoplasia, 7, 944–956.PubMedCrossRefGoogle Scholar
  34. 34.
    Pavelka, N., Rancati, G., Zhu, J., Bradford, W. D., Saraf, A., et al. (2010). Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast. Nature, 468, 321–325.PubMedCrossRefGoogle Scholar
  35. 35.
    Rancati, G., Pavelka, N., Fleharty, B., Noll, A., Trimble, R., et al. (2008). Aneuploidy underlies rapid adaptive evolution of yeast cells deprived of a conserved cytokinesis motor. Cell, 135, 879–893.PubMedCrossRefGoogle Scholar
  36. 36.
    Springer, M., Weissman, J. S., & Kirschner, M. W. (2010). A general lack of compensation for gene dosage in yeast. Mol Sys Biol, 6, 368.Google Scholar
  37. 37.
    Sheltzer, J. M., Torres, E. M., Dunham, M. J., & Amon, A. (2012). Transcriptional consequences of aneuploidy. Proceedings of the National Academy of Sciences, 109, 12644–12649.CrossRefGoogle Scholar
  38. 38.
    FitzPatrick, D. R., Ramsay, J., McGill, N. I., Shade, M., Carothers, A. D., et al. (2002). Transcriptome analysis of human autosomal trisomy. Human Molecular Genetics, 11, 3249–3256.PubMedCrossRefGoogle Scholar
  39. 39.
    Ait Yahya-Graison, E., Aubert, J., Dauphinot, L., Rivals, I., Prieur, M., et al. (2007). Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes. American Journal of Human Genetics, 81, 475–491.PubMedCrossRefGoogle Scholar
  40. 40.
    Stingele, S., Stoehr, G., Peplowska, K., Cox, J., Mann, M., et al. (2012). Global analysis of genome, transcriptome and proteome reveals the response to aneuploidy in human cells. Molecular Systems Biology, 8, 608.PubMedCrossRefGoogle Scholar
  41. 41.
    Kuijjer, M. L., Rydbeck, H., Kresse, S. H., Buddingh, E. P., Lid, A. B., et al. (2012). Identification of osteosarcoma driver genes by integrative analysis of copy number and gene expression data. Genes, Chromosomes & Cancer, 51, 696–706.CrossRefGoogle Scholar
  42. 42.
    Huang, S. (2009). Non-genetic heterogeneity of cells in development: more than just noise. Development, 136, 3853–3862.PubMedCrossRefGoogle Scholar
  43. 43.
    Chang, H. H., Hemberg, M., Barahona, M., Ingber, D. E., & Huang, S. (2008). Transcriptome-wide noise controls lineage choice in mammalian progenitor cells. Nature, 453, 544–547.PubMedCrossRefGoogle Scholar
  44. 44.
    Ye, C. J., Stevens, J. B., Liu, G., Bremer, S. W., Jaiswal, A. S., et al. (2009). Genome based cell population heterogeneity promotes tumorigenicity: the evolutionary mechanism of cancer. Journal of Cellular Physiology, 219, 288–300.PubMedCrossRefGoogle Scholar
  45. 45.
    Mi, R., Pan, C., Bian, X., Song, L., Tian, W., et al. (2012). Fusion between tumor cells enhances melanoma metastatic potential. Journal of Cancer Research and Clinical Oncology, 138, 1651–1658.PubMedCrossRefGoogle Scholar
  46. 46.
    Pinto, A. E., Silva, G. L., Pereira, T., Cabrera, R. A., Santos, J. R., et al. (2012). S-phase fraction and ploidy as predictive markers in primary disease and recurrence of papillary thyroid carcinoma. Clinical Endocrinology, 77, 302–309.PubMedCrossRefGoogle Scholar
  47. 47.
    Jasmine, F., Rahaman, R., Dodsworth, C., Roy, S., Paul, R., et al. (2012). A genome-wide study of cytogenetic changes in colorectal cancer using snp microarrays: opportunities for future personalized treatment. PloS One, 7, e31968.PubMedCrossRefGoogle Scholar
  48. 48.
    Duesberg, P., Li, R., Fabarius, A., & Hehlmann, R. (2006). Aneuploidy and cancer: from correlation to causation. Contributions to Microbiology, 13, 16–44.PubMedCrossRefGoogle Scholar
  49. 49.
    Braun, S., Auer, D., & Marth, C. (2009). The prognostic impact of bone marrow micrometastases in women with breast cancer. Cancer Investigation, 27, 598–603.PubMedCrossRefGoogle Scholar
  50. 50.
    Habermann, J. K., Paulsen, U., Roblick, U. J., Upender, M. B., McShane, L. M., et al. (2007). Stage-specific alterations of the genome, transcriptome, and proteome during colorectal carcinogenesis. Genes, Chromosomes & Cancer, 46, 10–26.CrossRefGoogle Scholar
  51. 51.
    Lu, X., Lu, X., & Kang, Y. (2010). Organ-specific enhancement of metastasis by spontaneous ploidy duplication and cell size enlargement. Cell Research, 20, 1012–1022.PubMedCrossRefGoogle Scholar
  52. 52.
    Adeyinka, A., Kytola, S., Mertens, F., Pandis, N., & Larsson, C. (2000). Spectral karyotyping and chromosome banding studies of primary breast carcinomas and their lymph node metastases. International Journal of Molecular Medicine, 5, 235–240.PubMedGoogle Scholar
  53. 53.
    Popescu, N. C., & Zimonjic, D. B. (2002). Chromosome and gene alterations in breast cancer as markers for diagnosis and prognosis as well as pathogenetic targets for therapy. American Journal of Medical Genetics, 115, 142–149.PubMedCrossRefGoogle Scholar
  54. 54.
    Bieche, I., & Lidereau, R. (1995). Genetic alterations in breast-cancer. Genes, Chromosomes & Cancer, 14, 227–251.CrossRefGoogle Scholar
  55. 55.
    Goodison, S., Viars, C., & Urquidi, V. (2005). Molecular cytogenetic analysis of a human breast metastasis model: identification of phenotype-specific chromosomal rearrangements. Cancer Genetics and Cytogenetics, 156, 37–48.PubMedCrossRefGoogle Scholar
  56. 56.
    Klein, C. A., Blankenstein, T. J., Schmidt-Kittler, O., Petronio, M., Polzer, B., et al. (2002). Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. Lancet, 360, 683–689.PubMedCrossRefGoogle Scholar
  57. 57.
    Malkhosyan, S., Yasuda, J., Soto, J. L., Sekiya, T., Yokota, J., et al. (1998). Molecular karyotype (amplotype) of metastatic colorectal cancer by unbiased arbitrarily primed PCR DNA fingerprinting. Proceedings of the National Academy of Sciences of the United States of America, 95, 10170–10175.PubMedCrossRefGoogle Scholar
  58. 58.
    Barbazan, J., Alonso-Alconada, L., Muinelo-Romay, L., Vieito, M., Abalo, A., et al. (2012). Molecular characterization of circulating tumor cells in human metastatic colorectal cancer. PloS One, 7, e40476.PubMedCrossRefGoogle Scholar
  59. 59.
    Gupta, G. P., Nguyen, D. X., Chiang, A. C., Bos, P. D., Kim, J. Y., et al. (2007). Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature, 446, 765–770.PubMedCrossRefGoogle Scholar
  60. 60.
    Lunt, S. J., Chaudary, N., & Hill, R. P. (2009). The tumor microenvironment and metastatic disease. Clinical & Experimental Metastasis, 26, 19–34.CrossRefGoogle Scholar
  61. 61.
    Ellsworth, R., Ellsworth, D., Patney, H., Deyarmin, B., Hooke, J., et al. (2008). Genomic alterations associated with early stages of breast tumor metastasis. Annals of Surgical Oncology, 15, 1989–1995.PubMedCrossRefGoogle Scholar
  62. 62.
    Heng, H.H., Bremer, S.W., Stevens, J.B., Horne, S.D., Liu, G., et al. (2013). Chromosomal instability (CIN): what is it and why it is crucial to cancer evolution. Cancer and Metastasis Reviews (in press).Google Scholar
  63. 63.
    Sethi, N., & Kang, Y. (2011). Unravelling the complexity of metastasis—molecular understanding and targeted therapies. Nature Reviews Cancer, 11, 735–748.PubMedCrossRefGoogle Scholar
  64. 64.
    Frost, P., Kerbel, R. S., Hunt, B., Man, S., & Pathak, S. (1987). Selection of metastatic variants with identifiable karyotypic changes from a nonmetastatic murine tumor after treatment with 2′-deoxy-5-azacytidine or hydroxyurea: implications for the mechanisms of tumor progression. Cancer Research, 47, 2690–2695.PubMedGoogle Scholar
  65. 65.
    Ince, T. A., Richardson, A. L., Bell, G. W., Saitoh, M., Godar, S., et al. (2007). Transformation of different human breast epithelial cell types leads to distinct tumor phenotypes. Cancer Cell, 12, 160–170.PubMedCrossRefGoogle Scholar
  66. 66.
    Ton, N. C., & Jayson, G. C. (2004). Resistance to anti-VEGF agents. Current Pharmaceutical Design, 10, 51–64.PubMedCrossRefGoogle Scholar
  67. 67.
    Horne, S.D., Stevens, J.B., Abdallah, B.Y., Liu, G., Bremer, S.W., et al. (2013). Why Gleevec remains the exception of cancer research—a genome-based evolutionary perspective. Journal of Cellular Physiology 228:665–670Google Scholar
  68. 68.
    Higgins, C. F. (2007). Multiple molecular mechanisms for multidrug resistance transporters. Nature, 446, 749–757.PubMedCrossRefGoogle Scholar
  69. 69.
    Duesberg, P., Stindl, R., & Hehlmann, R. (2001). Origin of multidrug resistance in cells with and without multidrug resistance genes: chromosome reassortments catalyzed by aneuploidy. Proceedings of the National Academy of Sciences of the United States of America, 98, 11283–11288.PubMedCrossRefGoogle Scholar
  70. 70.
    Heng, H.H., Liu, G., Stevens, J.B., Abdallah, B.Y., Horne, S.D., et al. (2013). Karyotype heterogeneity and unclassified chromosomal abnormalities. Cytogenetic and Genome Research, 2, 144–157.Google Scholar
  71. 71.
    Forment, J. V., Kaidi, A., & Jackson, S. P. (2012). Chromothripsis and cancer: causes and consequences of chromosome shattering. Nature Reviews Cancer, 12, 663–670.PubMedCrossRefGoogle Scholar
  72. 72.
    Foraker, A. B., Camus, S. M., Evans, T. M., Majeed, S. R., Chen, C.-Y., et al. (2012). Clathrin promotes centrosome integrity in early mitosis through stabilization of centrosomal ch-TOG. The Journal of Cell Biology, 198, 591–605.PubMedCrossRefGoogle Scholar
  73. 73.
    Maher, C. A., Palanisamy, N., Brenner, J. C., Cao, X., Kalyana-Sundaram, S., et al. (2009). Chimeric transcript discovery by paired-end transcriptome sequencing. Proceedings of the National Academy of Sciences of the United States of America, 106, 12353–12358.PubMedCrossRefGoogle Scholar
  74. 74.
    Maher, J., Brentjens, R. J., Gunset, G., Riviere, I., & Sadelain, M. (2002). Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCR[ζ]/CD28 receptor. Nature Biotechnology, 20, 70–75.PubMedCrossRefGoogle Scholar
  75. 75.
    Blount, Z. D., Barrick, J. E., Davidson, C. J., & Lenski, R. E. (2012). Genomic analysis of a key innovation in an experimental Escherichia coli population. Nature, 489, 513–518.PubMedCrossRefGoogle Scholar
  76. 76.
    Heng, H. H. (2009). The genome-centric concept: resynthesis of evolutionary theory. Bioessays, 31, 512–525.PubMedCrossRefGoogle Scholar
  77. 77.
    Gillies, R. J., Verduzco, D., & Gatenby, R. A. (2012). Evolutionary dynamics of carcinogenesis and why targeted therapy does not work. Nature Reviews Cancer, 12, 487–493.PubMedCrossRefGoogle Scholar
  78. 78.
    Heng, H.H. (2013). 4-D Genomics: genome dynamics and constraint in evolution: New York: SpringerGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Joshua B. Stevens
    • 1
  • Steven D. Horne
    • 1
  • Batoul Y. Abdallah
    • 1
  • Christine J. Ye
    • 2
  • Henry H. Heng
    • 1
    • 3
    • 4
  1. 1.Center for Molecular Medicine and GeneticsWayne State University School of MedicineDetroitUSA
  2. 2.Department of Internal MedicineWayne State University School of MedicineDetroitUSA
  3. 3.Department of PathologyWayne State University School of MedicineDetroitUSA
  4. 4.Karmanos Cancer InstituteDetroitUSA

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