Chromosomal Instability (CIN) in Cancer

Abstract

Chromosomal instability (CIN) represents a common feature in the majority of cancers. Despite that the search for specific molecular mechanisms linked to the causation or consequences of cancer has become very popular in cancer research, there is no general conceptual framework that unifies the observed diverse molecular findings. By applying the genome theory of cancer evolution, we briefly define and clarify CIN, synthesise its importance in macro‐cellular evolutionary selection, unify diverse molecular mechanisms under the evolutionary mechanism of cancer and discuss its potential implications. Understanding the relationship of stress, CIN and genome‐mediated cancer evolution offers clarity and direction to researchers, and monitoring CIN within an evolutionary context can provide valuable clinical information for determining treatment administration and patient prognosis.

Key Concepts

  • Chromosomal aberrations exist in the majority of cancers, suggesting the importance of understanding CIN in cancer.
  • Cancer genome evolution exists in two cyclical phases: a genome replacement mediated punctuated (macro‐cellular) phase and a gene/epigene‐mediated stepwise (micro‐cellular) phase; triggering CIN is the key to entering the macro‐cellular evolutionary phase.
  • CIN represents the key driver of cancer, as high levels rapidly produce wide varieties of new genome systems, providing necessary heterogeneity (and ample opportunity) for evolutionary selection.
  • Understanding the relationship among CIN, different genetic level dynamics and macro‐cellular evolution can be accomplished using multiple level landscape models.
  • Application of the evolutionary mechanism of cancer in understanding CIN offers clarity by unifying the wide variety of involved genetic and non‐genetic mechanisms and factors.
  • The consequences of high stress‐induced CIN (e.g. genome chaos, adaptation and accelerated macro‐cellular evolution) hold high implications in cancer treatment and drug resistance.
  • Fuzzy inheritance, which also reflects as elevated CIN at the genome level, represents a major mechanism of cancer evolution.
  • Monitoring CIN within an evolutionary context can provide valuable information for both cancer research and treatment.

Keywords: cancer evolution; chromosomal instability (CIN); clonal chromosome aberration (CCA); fuzzy inheritance; genome chaos; genome heterogeneity; genome theory; non‐clonal chromosome aberration (NCCA); system inheritance

Figure 1. The phenomenon of genome chaos generating new genetic systems. When CIN becomes extremely elevated under high stress, formation of chaotic genomes will be induced. The drastically altered genome will result in a new system with a newly formed network structure. (a) Spectral karyotype (SKY) image of genome chaos where massive translocation events are detected within a chaotic genome following drug treatment. These newly formed giant chromosomes are possibly derived from complex chromosomal fusion following chromosome fragmentation, with each colour representing their chromosomal origin. (b) The reverse DAPI image of the same mitotic figure in (a). (c) Schematic demonstrating how various forms of genome chaos may occur. Normal chromosomes are shown at the top, with each letter within the chromosomes representing a distinct region. Following exposure to sufficient degrees of various stressors, the genome undergoes partial fragmentation. Following fragmentation, regions are recombined and rejoined, resulting in the genome chaos demonstrated at the bottom. Newly formed chimeric chromosomes can be a mixture of various chromosomal origins, or occasionally from a single chromosome. (d) Changes in genome topology alter genetic network structure. For simplicity, two chromosomes are drawn within the nucleus, representing the genome. Genes are designated A, B, C, D and E within the chromosomes. When a translocation occurs, the genome topology is altered, affecting the physical relationship between chromatin domains and changing the overall genetic network structure. As a result, the genetic network changes (indicated by the altered relationship among proteins A, B, C, D and E). Thus, drastically altered genomes (products of genome chaos) represent new genome systems, and understanding this process provides insight into macro‐cellular cancer evolution. Reproduced with permission from Heng et al., 2011a,b © Elsevier.
Figure 2. Diagram illustrating the relationship among stress, diverse individual molecular mechanisms of cancer, CIN, and stochastic genome change‐mediated cancer evolution. The hallmarks of cancer (adapted from Hanahan and Weinberg, ) were used to represent different pathways linked to cancer. Stress is the motor that turns the pathway wheel. Selection of a given pathway as a mechanism of cancer progression is represented by the arrow which selects a pathway based on probability. Individual pathways can directly compromise genome integrity (type I) or indirectly jeopardise genome integrity through general stress (type II). Both types I and II CIN are linked to elevated NCCA frequency. Stress‐induced CIN is the key generator of evolutionary potential leading to macro‐cellular evolution. Reproduced with permission from Heng et al., 2013a © Springer Science+Business Media.
close

References

Abdallah BY, Horne SD, Stevens JB, et al. (2013) Single cell heterogeneity: why unstable genomes are incompatible with average profiles. Cell Cycle 12 (23): 3640–3649.

Abdallah BY, Horne SD, Liu G, et al. Fuzzy inheritance: a principal form of inheritance that regulates cell population/tumor heterogeneity. Submitted.

Baca SC, Prandi D, Lawrence MS, et al. (2013) Punctuated evolution of prostate cancer genomes. Cell 153 (3): 666–677.

Bayani J, Selvarajah S, Maire G, et al. (2007) Genomic mechanisms and measurement of structural and numerical instability in cancer cells. Seminars in Cancer Biology 17 (1): 5–18.

Biesterfeld S, Gerres K, Fischer‐Wein G and Böcking A (1994) Polyploidy in non‐neoplastic tissues. Journal of Clinical Pathology 47 (1): 38–42.

Burrell RA, McGranahan N, Bartek J and Swanton C (2013) The causes and consequences of genetic heterogeneity in cancer evolution. Nature 501 (7467): 338–345.

Celton‐Morizur S and Desdouets C (2010) Polyploidization of liver cells. Advances in Experimental Medicine and Biology 676: 123–135.

D'Amours D and Jackson SP (2002) The Mre11 complex: at the crossroads of dna repair and checkpoint signalling. Nature Reviews Molecular Cell Biology 3 (5): 317–327.

Davoli T and de Lange T (2011) The causes and consequences of polyploidy in normal development and cancer. Annual Review of Cell and Developmental Biology 27: 585–610.

Fragouli E and Wells D (2011) Aneuploidy in the human blastocyst. Cytogenetic and Genome Research 133 (2–4): 149–159.

Gatenby RA, Silva AS, Gillies RJ and Frieden BR (2009) Adaptive therapy. Cancer Research 69 (11): 4894–4903.

Gerlinger M, Rowan AJ, Horswell S, et al. (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. New England Journal of Medicine 366 (10): 883–892.

Hanahan D and Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144 (5): 646–674.

Hanks S, Coleman K, Reid S, et al. (2004) Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nature Genetics 36 (11): 1159–1161.

Heng HH (2007) Cancer genome sequencing: the challenges ahead. Bioessays 29 (8): 783–794.

Heng HH (2009) The genome‐centric concept: resynthesis of evolutionary theory. Bioessays 31 (5): 512–525.

Heng HH (2015) Debating Cancer: The Paradox in Cancer Research. Singapore: World Scientific Publishing Company.

Heng HH, Stevens JB, Liu G, et al. (2006) Stochastic cancer progression driven by non‐clonal chromosome aberrations. Journal of Cellular Physiology 208 (2): 461–472.

Heng HH, Stevens JB, Bremer SW, et al. (2011a) Evolutionary mechanisms and diversity in cancer. Advances in Cancer Research 112: 217–253.

Heng HH, Liu G, Stevens JB, et al. (2011b) Decoding the genome beyond sequencing: the new phase of genomic research. Genomics 98 (4): 242–252.

Heng HH, Bremer SW, Stevens JB, et al. (2013a) Chromosomal instability (CIN): what it is and why it is crucial to cancer evolution. Cancer and Metastasis Reviews 32 (3–4): 325–340.

Heng HH, Liu G, Stevens JB, et al. (2013b) Karyotype heterogeneity and unclassified chromosomal abnormalities. Cytogenetic and Genome Research 139 (3): 144–157.

Heng HH, Horne SD, Stevens JB, et al. (2015) Proceedings of the First International Conference on Systems and Complexity in Health, Washington, D.C. in press. New York: Springer.

Horne SD, Stevens JB, Abdallah BY, et al. (2013) Why imatinib remains an exception of cancer research. Journal of Cellular Physiology 228 (4): 665–670.

Horne SD, Chowdhury SK and Heng HH (2014) Stress, genomic adaptation, and the evolutionary trade‐off. Frontiers in Genetics 5 (92): 1–6.

Horne SD, Wexler M, Stevens JB and Heng HH (2015a) Insights on processes of evolutionary tumor growth. Atlas of Genetics and Cytogenetics in Oncology and Haematology, accessed on March 2015.

Horne SD, Ye CJ, Abdallah BY, Liu G and Heng HH (2015b) Cancer genome evolution. Translational Cancer Research 4 (3): 303–313.

Horne SD, Pollick SA and Heng HH (2015c) Evolutionary mechanism unifies the hallmarks of cancer. International Journal of Cancer 136 (9): 2012–2021.

Horne SD, Liu G, Abdallah BY, et al. Effective drug treatment drives rapid genome alteration‐mediated cancer evolution. Submitted.

Huang S (2013) Genetic and non‐genetic instability in tumor progression: link between the fitness landscape and the epigenetic landscape of cancer cells. Cancer and Metastasis Reviews 32 (3–4): 423–448.

Janssen A and Medema RH (2013) Genetic instability: tipping the balance. Oncogene 32: 4459–4470.

Kerbel RS and Kamen BA (2004) The anti‐angiogenic basis of metronomic chemotherapy. Nature Reviews Cancer 4 (6): 423–436.

Klein CA (2013) Selection and adaptation during metastatic cancer progression. Nature 501 (7467): 365–372.

Kolodner RD, Putnam CD and Myung K (2002) Maintenance of genome stability in Saccharomyces cerevisiae. Science 297 (5581): 552–557.

Liu G, Stevens JB, Horne SD, et al. (2014) Genome chaos: Survival strategy during crisis. Cell Cycle 13 (4): 528–537.

Navin N, Kendall J, Troge J, et al. (2011) Tumour evolution inferred by single‐cell sequencing. Nature 472 (7341): 90–94.

Pavelka N, Rancati G, Zhu J, et al. (2010) Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast. Nature 468 (7321): 321–325.

Pfau SJ and Amon A (2012) Chromosomal instability and aneuploidy in cancer: from yeast to man. EMBO Reports 13 (6): 515–527.

Roschke AV and Kirsch IR (2010) Targeting karyotypic complexity and chromosomal instability of cancer cells. Current Drug Targets 11 (10): 1341–1350.

Schmutte C (2005) Chromosomal instability (CIN) in cancer. In: eLS. Chichester: John Wiley & Sons, Ltd.

Sheffer M, Bacolod MD, Zuk O, et al. (2009) Association of survival and disease progression with chromosomal instability: a genomic exploration of colorectal cancer. Proceedings of the National Academy of Sciences 106 (17): 7131–7136.

Sottoriva A, Kang H, Ma Z, et al. (2015) A Big Bang model of human colorectal tumor growth. Nature Genetics 47 (3): 209–216.

Stephens PJ, Greenman CD, Fu B, et al. (2011) Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144 (1): 27–40.

Stevens JB, Liu G, Bremer SW, et al. (2007) Mitotic cell death by chromosome fragmentation. Cancer Research 67 (16): 7686–7694.

Stevens JB, Abdallah BY, Liu G, et al. (2011a) Diverse system stresses: common mechanisms of chromosome fragmentation. Cell Death and Disease 2: e178.

Stevens JB, Abdallah BY, Horne SD, et al. (2011b) Genetic and epigenetic heterogeneity in cancer. In: eLS. Chichester: John Wiley & Sons, Ltd.

Stevens JB, Liu G, Abdallah BY, et al. (2014) Unstable genomes elevate transcriptome dynamics. International Journal of Cancer 134 (9): 2074–2087.

van Brabant AJ, Stan R and Ellis NA (2000) DNA helicases, genomic instability, and human genetic disease. Annual Review of Genomics and Human Genetics 1: 409–459.

Wang Y, Waters J, Leung ML, et al. (2014) Clonal evolution in breast cancer revealed by single nucleus genome sequencing. Nature 512 (7513): 155–160.

Weaver BA and Cleveland DW (2007) Aneuploidy: instigator and inhibitor of tumorigenesis. Cancer Research 67 (21): 10103–10105.

Ye CJ, Liu G, Bremer SW and Heng HH (2007) The dynamics of cancer chromosomes and genomes. Cytogenetic and Genome Research 118 (2–4): 237–246.

Ye CJ, Stevens JB, Liu G, et al. (2009) Genome based cell population heterogeneity promotes tumorigenicity: the evolutionary mechanism of cancer. Journal of Cellular Physiology 219 (2): 288–300.

Further Reading

Breivik J (2001) Don't stop for repairs in a war zone: Darwinian evolution unites genes and environment in cancer development. Proceedings of the National Academy of Sciences 98 (10): 5379–5381.

Duesberg P (2007) Chromosomal chaos and cancer. Scientific American 296 (8): 52–59.

Gibbs WW (2003) Untangling the roots of cancer. Scientific American 289 (1): 56–65.

Gisselsson D (2001) Chromosomal instability in cancer: causes and consequences. Atlas of Genetics and Cytogenetics in Oncology and Haematology 5 (3): 237–244.

Heng HH, Stevens JB, Bremer SW, et al. (2010) The evolutionary mechanism of cancer. Journal of Cellular Biochemistry 109 (6): 1072–1084.

Iourov IY, Vorsanova SG and Yurov YB (2008) Chromosomal mosaicism goes global. Molecular Cytogenetics 1: 26.

Lengauer C, Kinzler KW and Vogelstein B (1998) Genetic instabilities in human cancers. Nature 396 (6712): 643–649.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Horne, Steven D, Ye, Christine J, and Heng, Henry HQ(Nov 2015) Chromosomal Instability (CIN) in Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006069.pub2]