Harvard College, 86 Brattle Street Cambridge, MA, 02138, USA.
Molecular Medicine and Genomics, Wayne State University School of Medicine, Detroit, MI, 48201, USA; Department of Pathology, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
Prog Biophys Mol Biol. 2021 Oct;165:29-42. doi: 10.1016/j.pbiomolbio.2021.04.003. Epub 2021 May 13.
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.
癌症传统上被标记为“细胞生长问题”。然而，它从根本上说是一个宏观进化问题，新系统通过打破各种限制从组织中出现。为了研究这个过程，我们使用实验平台通过比较核型、转录组和细胞表型的纵向特征，在关键相变之前、期间和之后，“观察进化的实际情况”。这项工作，以及对当前基于基因的基因组和进化理论的批判性重新思考，导致了基因组结构理论的发展。在简要回顾历史之后，我们提出了四个案例研究及其要点，以描述基于基因组的癌症进化模式。我们的发现包括：1. 非克隆染色体畸变或 NCCAs 的重要性；2. 两阶段癌症进化，包括一个突发阶段和一个渐进阶段，分别由核型变化和基因突变/表观遗传改变主导；3. 核型如何编码系统遗传，组织基因相互作用并为生理调节网络提供基因组基础；4. 应激诱导的基因组混乱，通过重新组织染色体为宏观进化创造基因组信息。这些案例研究共同重新定义了细胞宏观进化和微观进化之间的关系：宏观进化不等于微观进化+时间。此外，我们将基因组混乱和基因突变纳入一般模型：基因组重组创建新的核型编码，然后多样化的癌症基因突变可以促进肿瘤细胞群体的优势。最后，我们呼吁验证癌症和生物体进化的基因组结构理论，以及系统研究进化过程中的基因组信息流。
