Genomic destabilization and its associated mutagenesis increase with senescence‐associated phenotype expression

Cancer develops through multiple rounds of clonal evolution of cells with abrogated defense systems. Such clonal evolution is triggered by genomic destabilization with associated mutagenesis. However, what increases the risk of genomic destabilization remains unclear. Genomic instability is usually the result of erroneous repair of DNA double‐strand breaks (DSB); paradoxically, however, most cancers develop with genomic instability but lack mutations in DNA repair systems. In this manuscript, we review current knowledge regarding a cellular state that increases the risk of genomic destabilization, in which cells exhibit phenotypes often observed during senescence. In addition, we explore the pathways that lead to genomic destabilization and its associated mutagenesis, which ultimately result in cancer. Genomic destabilization risk is elevated in association with cellular senescence. Genomic destabilization is associated with mutagenesis. Genomic destabilization induces clonal evolution of cells with abrogated defense systems.