Genome Chaos, Information Creation, and Cancer Emergence: Searching for New Frameworks on the 50th Anniversary of the “War on Cancer”

The year 2021 marks the 50th anniversary of the National Cancer Act, signed by President Nixon, which declared a national “war on cancer.” Powered by enormous financial support, this past half-century has witnessed remarkable progress in understanding the individual molecular mechanisms of cancer, primarily through the characterization of cancer genes and the phenotypes associated with their pathways. Despite millions of publications and the overwhelming volume data generated from the Cancer Genome Project, clinical benefits are still lacking. In fact, the massive, diverse data also unexpectedly challenge the current somatic gene mutation theory of cancer, as well as the initial rationales behind sequencing so many cancer samples. Therefore, what should we do next? Should we continue to sequence more samples and push for further molecular characterizations, or should we take a moment to pause and think about the biological meaning of the data we have, integrating new ideas in cancer biology? On this special anniversary, we implore that it is time for the latter. We review the Genome Architecture Theory, an alternative conceptual framework that departs from gene-based theories. Specifically, we discuss the relationship between genes, genomes, and information-based platforms for future cancer research. This discussion will reinforce some newly proposed concepts that are essential for advancing cancer research, including two-phased cancer evolution (which reconciles evolutionary contributions from karyotypes and genes), stress-induced genome chaos (which creates new system information essential for macroevolution), the evolutionary mechanism of cancer (which unifies diverse molecular mechanisms to create new karyotype coding during evolution), and cellular adaptation and cancer emergence (which explains why cancer exists in the first place). We hope that these ideas will usher in new genomic and evolutionary conceptual frameworks and strategies for the next 50 years of cancer research.

How Chaotic Is Genome Chaos?

Cancer genomes evolve in a punctuated manner during tumor evolution. Abrupt genome restructuring at key steps in this evolution has been called “genome chaos.” To answer whether widespread genome change is truly chaotic, this review (i) summarizes the limited number of cell and molecular systems that execute genome restructuring, (ii) describes the characteristic signatures of DNA changes that result from activity of those systems, and (iii) examines two cases where genome restructuring is determined to a significant degree by cell type or viral infection. The conclusion is that many restructured cancer genomes display sufficiently unchaotic signatures to identify the cellular systems responsible for major oncogenic transitions, thereby identifying possible targets for therapies to inhibit tumor progression to greater aggressiveness.

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

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.

From Genes to Genomes

In Genome Chaos: Rethinking Genetics, Evolution, and Molecular Medicine, Henry Heng invites readers to herald a new age in how biologists consider the genome. He reframes the genome’s role in determining the hereditary properties of cells and organisms, while also challenging popular notions of the genotype–phenotype relationship. Reviewer James Shapiro applauds Heng’s novel approach.

Micronuclei and Genome Chaos: Changing the System Inheritance

Micronuclei research has regained its popularity due to the realization that genome chaos, a rapid and massive genome re-organization under stress, represents a major common mechanism for punctuated cancer evolution. The molecular link between micronuclei and chromothripsis (one subtype of genome chaos which has a selection advantage due to the limited local scales of chromosome re-organization), has recently become a hot topic, especially since the link between micronuclei and immune activation has been identified. Many diverse molecular mechanisms have been illustrated to explain the causative relationship between micronuclei and genome chaos. However, the newly revealed complexity also causes confusion regarding the common mechanisms of micronuclei and their impact on genomic systems. To make sense of these diverse and even conflicting observations, the genome theory is applied in order to explain a stress mediated common mechanism of the generation of micronuclei and their contribution to somatic evolution by altering the original set of information and system inheritance in which cellular selection functions. To achieve this goal, a history and a current new trend of micronuclei research is briefly reviewed, followed by a review of arising key issues essential in advancing the field, including the re-classification of micronuclei and how to unify diverse molecular characterizations. The mechanistic understanding of micronuclei and their biological function is re-examined based on the genome theory. Specifically, such analyses propose that micronuclei represent an effective way in changing the system inheritance by altering the coding of chromosomes, which belongs to the common evolutionary mechanism of cellular adaptation and its trade-off. Further studies of the role of micronuclei in disease need to be focused on the behavior of the adaptive system rather than specific molecular mechanisms that generate micronuclei. This new model can clarify issues important to stress induced micronuclei and genome instability, the formation and maintenance of genomic information, and cellular evolution essential in many common and complex diseases such as cancer.