Origins and Consequences of Chromosomal Instability: From Cellular Adaptation to Genome Chaos-Mediated System Survival

Abstract

When discussing chromosomal instability, most of the literature focuses on the characterization of individual molecular mechanisms. These studies search for genomic and environmental causes and consequences of chromosomal instability in cancer, aiming to identify key triggering factors useful to control chromosomal instability and apply this knowledge in the clinic. Since cancer is a phenomenon of new system emergence from normal tissue driven by somatic evolution, such studies should be done in the context of new genome system emergence during evolution. In this perspective, both the origin and key outcome of chromosomal instability are examined using the genome theory of cancer evolution. Specifically, chromosomal instability was linked to a spectrum of genomic and non-genomic variants, from epigenetic alterations to drastic genome chaos. These highly diverse factors were then unified by the evolutionary mechanism of cancer. Following identification of the hidden link between cellular adaptation (positive and essential) and its trade-off (unavoidable and negative) of chromosomal instability, why chromosomal instability is the main player in the macro-cellular evolution of cancer is briefly discussed. Finally, new research directions are suggested, including searching for a common mechanism of evolutionary phase transition, establishing chromosomal instability as an evolutionary biomarker, validating the new two-phase evolutionary model of cancer, and applying such a model to improve clinical outcomes and to understand the genome-defined mechanism of organismal evolution.

Tumour Evolution and Seed and Soil Mechanism in Pancreatic Metastases of Renal Cell Carcinoma

“…The two-phase cancer evolutionary model mentioned at the beginning, which combines the phase of a genome mediated, punctuated cellular macro-evolution and a subsequent phase of a gene mediated stepwise micro-evolution, can of course also serve to describe and explain the relationship between “seed and soil”. First, the punctuated macro-evolution phase leads (by chromosomal chaos—chromosomal re-organisation [ 4 ]) to the generation of new genomes and thus “new” cell species of great heterogeneity [ 6 ] with different metastatic properties (seed). Subsequently, the stepwise micro-evolution phase allows the growth of suitable tumour cell populations to metastases only in interaction with suitable host organ/tissue (soil).…”

“…Genetics thus provides for larger or smaller variations in living beings and the environment for the selection of the best adapted organisms. Malignant tumours—i.e., newly emerged cell clones that are genetically in some aspects different from the organism of origin and independent of its control mechanisms—can also be regarded as “new organisms” within an organism in a somewhat exaggerated way [ 1 , 2 , 3 , 4 , 5 , 6 ]. It is therefore not surprising that both mechanisms also play an important role in the metastasis behaviour of carcinomas.…”

“…The genetically determined development of tumour cells capable of metastases is currently explained by two models. The traditional linear stepwise “Neo-Darwinian” clonal expansions model [ 6 ], which has been accepted for a long time, has recently been contrasted with a two-phase cancer evolutionary model [ 5 , 6 , 7 , 8 ] consisting of genome reorganisation [ 5 ] mediated punctuated macro-evolution, followed by gene mutation/epigenetic-based stepwise micro-evolution [ 4 , 6 ].…”

Understanding How Genetic Mutations Collaborate with Genomic Instability in Cancer

“…When comparing the findings between models for stable aneuploidy and ongoing CIN (the latter extensively discussed elsewhere [28,29]), it appears that similar pathways are deregulated. However, mapping the consequences for ongoing CIN is complicated by the intrinsically heterogenous nature of the models.…”

Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

“…In fact, as shown in Figure 4 , in FA cells, CIN constantly generates cells with different karyotypes due to non-clonal chromosomal alterations. These gross changes in the karyotype are important, since each cell has a specific genome reorganization that generates a new genome system [ 117 ].…”