Abstract
Chromosome instability (CIN) refers to an ongoing rate of chromosomal changes and is a driver of genetic, cell-to-cell heterogeneity. It is an aberrant phenotype that is intimately associated with cancer development and progression. The presence, extent, and level of CIN has tremendous implications for the clinical management and outcomes of those living with cancer. Despite its relevance in cancer, there is still extensive misuse of the term CIN, and this has adversely impacted our ability to identify and characterize the molecular determinants of CIN. Though several decades of genetic research have provided insight into CIN, the molecular determinants remain largely unknown, which severely limits its clinical potential. In this review, we provide a definition of CIN, describe the two main types, and discuss how it differs from aneuploidy. We subsequently detail its impact on cancer development and progression, and describe how it influences metastatic potential with reference to cancer prognosis and outcomes. Finally, we end with a discussion of how CIN induces genetic heterogeneity to influence the use and efficacy of several precision medicine strategies, including patient and risk stratification, as well as its impact on the acquisition of drug resistance and disease recurrence.
Highlights
For over a century, cancer researchers and oncologists have sought to identify and characterize the molecular determinants driving cancer development and progression to influence health outcomes
This quest was fueled by the singular goal of identifying the genetic aberrations exhibiting similar causal relationships in other cancer types; it became readily apparent that this cause (BCR:ABL) and effect relationship was more an exception than the rule
There is a resurgence and increasing research focus on the impact Chromosome instability (CIN) has on cancer development and clinical outcomes
Summary
Cancer researchers and oncologists have sought to identify and characterize the molecular determinants (e.g., defective genes, proteins, and cellular pathways) driving cancer development and progression to influence health outcomes. Many cancers exhibit a striking degree of genetic heterogeneity encompassing both small (e.g., single nucleotide alterations, small insertions, or deletions) and large (e.g., gene amplifications/deletions, complex chromosome alterations, and whole chromosome gains/losses) scale alterations. This degree of genetic complexity challenged the classically held belief that genetic alterations of only a small subset of genes were required to drive cancer pathogenesis [5]. It should be noted that N- and S-CIN are not mutually exclusive, and that both can co-exist within a given cell or tumor (reviewed in [11])
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