Niche stem cell clonal evolution. A: A hypothetical niche with three stem cells. In niches, stem cell numbers rather than lineages are constant. With stem cell division, half the daughter cells leave the niche and differentiate. B: Stem cell lineages are distinguished by different colors. Niche stem cells are maintained by a population mechanism rather than strictly asymmetric divisions. Sometimes both daughter cells leave the niche (lineage extinction), balanced by two daughter cells that remain within the niche (lineage expansion). Eventually clonal evolution occurs when all but one present day stem cell lineage becomes extinct, which appears to recur about every eight years in human crypts . C: Crypt stem cell clonal evolution complicates mutation accumulation because most mutations are lost when their stem cells become extinct. Early mutations can only accumulate or become fixed if they occur in the stem cell that attains clonal dominance. A driver change acquired early in life therefore requires both mutation and fixation, which may help explain why the increased cancer incidence with aging appears to occur through multiple distinct rate-limiting stages . D: Crypt stem cell clonal evolution appears to take longer after an APC mutation, which decreases the likelihood that the next driver mutation will be lost before transformation. Certain APC mutations may shorten pathways to cancer because they are present in nearly all colorectal cancer genomes.