Chromosomal Instability (CIN) in Cancer


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.


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