Rethinking cancer initiation: The role of large-scale mutational events

Cancer initiation is revisited in light of recent discoveries in cancer pathogenesis. Of note is the detection of mutated cancer genes in benign conditions. More significantly, somatic clones, which harbor mutations in cancer genes, arise in normal tissues from early development through adulthood, but seldom do they transform into cancer. Further, clustered mutational events-kataegis, chromothripsis and chromoplexy-are widespread in cancer, generating point mutations and chromosomal rearrangements in a single cellular catastrophe. These observations are contrary to the prevailing somatic mutation theory, which states that a cancer is caused by the gradual accumulation of mutations over time. A different perspective is proposed within the framework of Waddington's epigenetic landscape wherein tumorigenesis is viewed primarily as a disruption of cell development. Cell types are defined by their specific gene-expression profiles, determined by the gene regulatory network, and can be regarded as attractor states of the network dynamics: they represent specific, self-stabilizing patterns of gene activities across the genome. However, large-scale mutational events reshape the landscape topology, creating abnormal "unphysiological" attractors. This is the crux of the process of initiation. Initiation primes the cell for conversion into a tumor phenotype by oncogenes and tumor suppressor genes, which drive cell proliferation and clonal diversification. This view of tumorigenesis calls for a different approach to therapy.