Cancer genome evolution

Cancer genome sequencing efforts have resulted in high amounts of diverse, conflicting genomic data, which ultimately challenge the gene mutation theory of cancer. Since each tumor is different, and the genomic landscape of cancer is highly dynamic, a new evolutionary framework and approaches are required to unify the field. While many recent publications of cancer genome sequencing data have addressed cancer genome evolution, there is no clear definition and a lack of systematic analyses, as the true evolutionary meaning of these massive genetic and epigenetic changes has been largely ignored in the search for specific drivers. Furthermore, there is a common confusion between traditional, Darwinian stepwise evolution and stochastic, punctuated cancer evolution. Herein, the genome theory, an emerging holistic theory that covers multiple levels of genetic and non-genetic alteration by shifting emphasis onto genome-defined (sequence and three-dimensional topology) system inheritance, is presented as a refreshing and promising new framework. Specifically, following introduction of the importance of the genetic information defined by the genome, the newly discovered pattern of cancer evolution (including the two phases of cancer evolution) and its genetic basis (including fuzzy inheritance) are described, which were recently confirmed by single-cell level DNA sequencing and explain how genome and gene/epigene level heterogeneity drive macro- and micro-cellular evolution. From these new understandings, both the limitations of current methodologies and new strategies are discussed. Finally, we suggest that understanding cancer evolution holds the key to understanding other complex diseases and evolutionary theory in general.