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One of the biggest surprises that came from the cancer genome sequencing project was the rediscovery of the chaotic genome. These rapidly generated and massively re-organized genomes have been detected within various types of cancer, and in some cancer types, chaotic genomes have been displayed in the majority of cases.14 To describe these fragmented and stitched chromosomes, many names have been given including“chromothripsis”, “chromoplexy”, “chromoanasynthesis”, “chromoanagenesis”, “chromosome catastrophes”, and “structural mutations”.1,415 These recent studies clearly reflect the interest towards these genome level alterations, as they might offer a new mechanism of cancer formation by non-traditional stepwise accumulation of gene mutations. This increased interest has been evidenced by a large number of high profile publications, however it seems that there are more reviews than hardcore mechanistic research papers.

Despite the many new terms that have been recently introduced, chaotic genomes are not new to cancer cytogenetic researchers. In fact, these complicated karyotypes have been reported and linked to some aggressive cancer cases and poor prognoses. They have even been observed in cultured lymphocytes from normal individuals after radiation exposure. Interestingly, these extensive chromosomal changes have been linked to high levels of chromosomal instability (CIN), and in particular, have been linked to the punctuated cancer evolutionary phase.16 In these studies, the terminology of “karyotypic chaos” was initially used, however, these have also been referred to as “chromosome chaos” or “genome chaos”.2,17,18 It is clear that these massive stochastic genome changes are often generated during the macro-cellular evolutionary phase and are essential for cancer evolution. In addition, these can be induced by drug treatment and are associated with rapid drug resistance.18 However, the exact molecular mechanism is less understood.

Unfortunately, the importance of genome chaos to cancer evolution was not immediately appreciated. In the face of massive changes, it is hard to identify impacted genes, and the stochastic nature of this process does not provide a fixed common pattern. Furthermore, since these changes are so drastic, they could be dismissed as merely in vitro artifacts. Therefore, these chaotic genomes must be eliminated by cell death mechanisms in patients, as it is extremely difficult to capture and image such drastic changes, which as many would argue are very meaningful. According to current evolutionary thinking, these massive genome alterations would not provide positive selective advantages.

Now, the concept of genome chaos is ready to be generally accepted as molecular tools have discovered and confirmed its presence within a large number of clinical samples. Indeed, it must be a real and important phenomenon. All of a sudden, this new phenomenon makes sense to researchers and has emerged as a hot topic of study. While exciting, the mechanism of genome chaos cannot be understood only by comparing sequences, especially when chaotic genomes represent the stochastic genome alterations during cancer evolution where genome level convergence is limited. Furthermore, there is no framework to explain their importance other than linking them with some known gene mutations, knowing that so many genes can be involved in such an event. As a result, chaotic genomes have been linked to specific gene mutations or pathways.

To solve this problem, an experimental system was recently introduced to trace the entire process of genome chaos and to study its molecular mechanisms in an evolutionary context.19 It was illustrated that genome chaos represents a survival strategy when cells undergo extremely high levels of stress. Non-homologous end joining is involved to form highly re-organized genomes following induced chromosome fragmentation, a newly identified type of mitotic cell death that differs from premature chromosome condensation.2023 Diverse molecular mechanisms can lead to genome chaos, and the evolutionary mechanism is needed to unify the large number of molecular mechanisms. Despite the massive cell death that can occur with high levels of stress, new genomes can form and thrive as a result of genome chaos.

In order to fully appreciate the importance of genome chaos, research should not only focus on the impacted genes, but should also incorporate the new concept of genome topology-defined system inheritance. According to the genome theory of cancer evolution:

1) New karyotypes define new system inheritance, as similar gene content can result in different inheritance by simply changing the genomic topology (or relationship among gene interaction2,24 For example, the main function of sex in organismal evolution is to preserve the karyotype, thus preserving system inheritance.2,2527 In contrast, for cancer evolution to be successful, the genome needs to be changed to form new systems, as the drastically altered chromosome structure itself (karyotype) functions as a systems oncogenic organizer.8

2) Genome chaos is often associated with macro-cellular evolution (punctuated evolution), where rapid and massive genome fragmentation and re-organization is needed for survival. This is different from stepwise micro-cellular evolution, which involves the accumulation of small changes (e.g. gene/epigene level). The two phases of cancer evolution were recently confirmed using cancer genome sequencing.28,29

3) Transcriptome dynamics are linked to evolutionary potential and provide explanation as to why different molecular pathways can be expressed in winning cells after selection.30 This concept is well illustrated using multiple level landscape models.2,31,32

4) Recent studies of cell population outliers have demonstrated the power of the individual chaotic genome in macro-cellular evolution,33 which explains why evolution can succeed despite the massive cell death coupled with genome chaos. While unstable, these genomes can rapidly evolve until stable clones emerge and thrive, representing the only chance for survival under crisis.

5) Genome alteration has adaptive function under stress.34 This sheds light on a key paradox of current aggressive therapeutic strategies, where high initial cell death consistently results in drug resistance. Despite early massive tumor cell killing, surviving populations after drug-induced genome chaos emerge and drive population growth and disease progression.

With these recent discoveries, we must reconsider our current framework, research strategies and practices regarding gene-based research in cancer. Considering the heterogeneity and large-scale genomic changes that are characteristic of the disease, what is the real impact of specific gene mutations in cancer. Since the genomic topology can vary drastically from one cell to the next with different system inheritance, and the same gene can play different roles depending on the genome context, characterizing these individual genes without considering genome-level alteration (the big elephant in the room) does not make sense. Even though we have some excellent examples of success, most of them represent exceptional cases with linear patterns of somatic cell evolution.35 By and large, cancer gene mutations represent moving targets. We must adopt a new strategy that integrates multiple level landscape models, which will not only account for the fitness of the disease, but also the survival landscape. We must also keep in mind that gross genomic alterations differ from small-scale changes such as copy number variation, as the same copy numbers can form different genome topologies. System inheritance is not only about new mutations and dosage of specific genes, but the new platform or structure of network dynamics.24 Finally, considering that decreased frequencies of genome chaos are detected at later stages, we can propose that this phenomenon is much more common in cancer than what sequencing has shown.19

In closing, the chaotic genome presents both challenges and opportunities for current cancer research. At the conceptual level, it shines new light on the novel pattern of somatic cell evolution, which differs from the traditional Darwinian framework, where the accumulation of small changes over time is the key (e.g. gene mutations over generations). However, macro-cellular evolution does not follow Darwinian evolution, as large-scale change can and often must be achieved within a short period of time. The survival landscape (often in the macro-cellular phase) differs from the fitness landscape (often in the micro-cellular phase). Understanding the two phases of cancer evolution is the key to appreciating the contribution of genome rearrangements.36

At the practical implication level, even though genome chaos limits the application of gene-centric cancer research, it also offers a new way of thinking in cancer.37 For example, the evolutionary mechanism of cancer unifies the various molecular mechanisms of cancer, 38,39 therefore there is no need to profile hundreds of thousands of samples and study every possible combination of gene mutations. The degree of genome instability can be used to predict tumorigenicity without the need to search for specific molecular pathways, and the degree of heterogeneity and complexity should serve as a universal biomarker for cancer evolution.31 One good example is how to deal with genome chaos-mediated drug resistance. On one hand, stress-induced genome chaos can lead to rapid drug resistance, one of the key hindrances of current cancer therapeutics. This notion that drug resistance is an adaptive process induced by the agents administered (in particular, when applied at maximum tolerated doses) provides reasoning for the paradoxical relationship between initial effective cell killing and consistent long-term resistance against all current approaches. On the other hand, knowng the contribution of genome chaos to drug resistance provides explanation behind the early successes and promise of alternative, less aggressive therapies (e.g. adaptive, metronomic).4042 Further studies that focus on how to avoid or reduce genome chaos induction while slowing down or constraining cancer should be clinically significant. Overall cancer genome stability and likelihood of triggering genome chaos would be useful measurements to screen for patients who should not undergo aggressive treatment regimens.

Welcome to the genome era of cancer research!