Two-phased evolution: Genome chaos-mediated information creation and maintenance.

Cancer is traditionally labeled a "cellular growth problem." However, it is fundamentally an issue of macroevolution where new systems emerge from tissue by breaking various constraints. To study this process, we used experimental platforms to "watch evolution in action" by comparing the profiles of karyotypes, transcriptomes, and cellular phenotypes longitudinally before, during, and after key phase transitions. This effort, alongside critical rethinking of current gene-based genomic and evolutionary theory, led to the development of the Genome Architecture Theory. Following a brief historical review, we present four case studies and their takeaways to describe the pattern of genome-based cancer evolution. Our discoveries include 1. The importance of non-clonal chromosome aberrations or NCCAs; 2. Two-phased cancer evolution, comprising a punctuated phase and a gradual phase, dominated by karyotype changes and gene mutation/epigenetic alterations, respectively; 3. How the karyotype codes system inheritance, which organizes gene interactions and provides the genomic basis for physiological regulatory networks; and 4. Stress-induced genome chaos, which creates genomic information by reorganizing chromosomes for macroevolution. Together, these case studies redefine the relationship between cellular macro- and microevolution: macroevolution does not equal microevolution + time. Furthermore, we incorporate genome chaos and gene mutation in a general model: genome reorganization creates new karyotype coding, then diverse cancer gene mutations can promote the dominance of tumor cell populations. Finally, we call for validation of the Genome Architecture Theory of cancer and organismal evolution, as well as the systematic study of genomic information flow in evolutionary processes.