Pathogenesis of clonal evolution. Top, clonal evolution represents an escape mechanism from immune pressure exerted by the immune system. In this process, antigens on normal stem cells or tumor-associated antigens can trigger the autoimmune attack or unselective tumor immune surveillance response, respectively. Bottom, clonal initiation due to recruitment of a defective stem cells in the context of a contracted stem cell pool, clonal promotion in a pro-oncogenic milieu due to increased growth factor drive and increased cycling to keep up with the demand, and increased rate of chromosomal defects leading to clonal expansion in the context of excessive telomere shortening or endogenous oncogenesis during inflammatory reactions.