The Importance of Henry H. Heng's Genome Architecture Theory.

A recent symposium on cancer and evolution has bought many innovative thinkers together to challenge the status quo of current cancer research. Professor Henry Heng's presentation considers cancer as a new system emerging via macro-evolution, where genome chaos-mediated information creation and maintenance plays an important role. This concept departs from the neo-Darwinian influenced somatic mutation theory of cancer. To appreciate his theory, it is helpful to briefly review several of his heterodox findings in the fields of oncology and evolutionary biology. This letter summarizes and highlights these findings and calls for a medical and scientific reckoning as well as integration within and between these fields.

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.

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.

Evolutionary mechanism unifies the hallmarks of cancer.

The basis for the gene mutation theory of cancer that dominates current molecular cancer research consists of: the belief that gene-level aberrations such as mutations are the main cause of cancers, the concept that stepwise gene mutation accumulation drives cancer progression, and the hallmarks of cancer. The research community swiftly embraced the hallmarks of cancer, as such synthesis has supported the notions that common cancer genes are responsible for the majority of cancers and the complexity of cancer can be dissected into simplified molecular principles. The gene/pathway classification based on individual hallmarks provides explanation for the large number of diverse gene mutations, which is in contrast to the original estimation that only a handful of gene mutations would be discovered. Further, these hallmarks have been highly influential as they also provide the rationale and research direction for continued gene-based cancer research. While the molecular knowledge of these hallmarks is drastically increasing, the clinical implication remains limited, as cancer dynamics cannot be summarized by a few isolated/fixed molecular principles. Furthermore, the highly heterogeneous genetic signature of cancers, including massive stochastic genome alterations, challenges the utility of continuously studying each individual gene mutation under the framework of these hallmarks. It is therefore necessary to re-evaluate the concept of cancer hallmarks through the lens of cancer evolution. In this analysis, the evolutionary basis for the hallmarks of cancer will be discussed and the evolutionary mechanism of cancer suggested by the genome theory will be employed to unify the diverse molecular mechanisms of cancer.