Patterns of Genome Dynamics and Cancer Evolution

The importance of the chromosome versus the gene as a causative agent in cancer formation has sparked a heated debate. This issue is directly related to two different schools of thought, namely the gene-centric or genome-centric paradigms of cancer research [1–3]. For decades we have essentially ignored the evolutionary nature of complex cancer systems due to the influence of reductionist viewpoints and experimental approaches. Cancer research has focused on identifying and characterizing the step-wise accumulation of gene mutations and the consequent effects on the corresponding pathways, as the cancer evolutionary process has been thought by many as a linear and predictable process. Despite the fact that chromosome aberrations are nearly universally detected in cancer cases, the gene-centric viewpoint has led to the conclusion that chromosome aberrations are a consequence of gene mutations and therefore must be late events. Furthermore , chromosomal research has focused on the identification of recurrent types of clonal chromosome aberrations (CCAs). Specific patterns of these clonal events have been utilized both in clinical diagnosis and treatment. However, due to hyper-focus on identifying recurrent changes, the true karyotypic heterogeneity of cancer has been under appreciated, with non-recurrent change being considered " genetic noise " , which has been largely ignored [4]. Recently, the existence of an overwhelming amount of non-clonal chromosome aberrations (NCCAs), the major form of genome variation and the key index for system instability, has been identified in patients and cancer progression models [5,6]. The study of chromosomes in cancer has also been considered a low resolution approach compared with molecular methods such as DNA sequencing and thus was said to not offer causative insight. However , mounting evidence (including the failure to identify a number of common causative gene mutations from large scale gene sequencing) shows that the long sought handful of mutated cancer causing genes does not exist [7,8]. This surprising finding is explained (and in fact has been predicted) through our demonstration that the stochastic karyotypic/genetic variation drives cancer progression and that cancer evolution through natural selection is mainly mediated by sto-chastic genome variation [2,6]. This crucial conclusion shows that cancer should be treated as an unpredictable evolutionary process of a complex system. These re-alizations challenge the strategies of solely pushing for higher resolution to/at the molecular level. From a complex system point of view, focusing on the details of the lower level (genes) might not reveal the emergent properties at the …