Genome chaos: Creating new genomic information essential for cancer macroevolution

Abstract

Cancer research has traditionally focused on the characterization of individual molecular mechanisms that can contribute to cancer. Due to the multiple levels of genomic and non-genomic heterogeneity, however, overwhelming molecular mechanisms have been identified, most with low clinical predictability. It is thus necessary to search for new concepts to unify these diverse mechanisms and develop better strategies to understand and treat cancer. In recent years, two-phased cancer evolution (comprised of the genome reorganization-mediated punctuated phase and gene mutation-mediated stepwise phase), initially described by tracing karyotype evolution, was confirmed by the Cancer Genome Project. In particular, genome chaos, the process of rapid and massive genome reorganization, has been commonly detected in various cancers-especially during key phase transitions, including cellular transformation, metastasis, and drug resistance-suggesting the importance of genome-level changes in cancer evolution. In this Perspective, genome chaos is used as a discussion point to illustrate new genome-mediated somatic evolutionary frameworks. By rephrasing cancer as a new system emergent from normal tissue, we present the multiple levels (or scales) of genomic and non-genomic information. Of these levels, evolutionary studies at the chromosomal level are determined to be of ultimate importance, since altered genomes change the karyotype coding and karyotype change is the key event for punctuated cellular macroevolution. Using this lens, we differentiate and analyze developmental processes and cancer evolution, as well as compare the informational relationship between genome chaos and its various subtypes in the context of macroevolution under crisis. Furthermore, the process of deterministic genome chaos is discussed to interpret apparently random events (including stressors, chromosomal variation subtypes, surviving cells with new karyotypes, and emergent stable cellular populations) as nonrandom patterns, which supports the new cancer evolutionary model that unifies genome and gene contributions during different phases of cancer evolution. Finally, the new perspective of using cancer as a model for organismal evolution is briefly addressed, emphasizing the Genome Theory as a new and necessary conceptual framework for future research and its practical implications, not only in cancer but evolutionary biology as a whole.

Keywords: Genome theory; Karyotype coding; Phase transition; Punctuated cellular macroevolution; Two phased cancer evolution.