Pre-tumor progression: clonal evolution of human stem cell populations

Multistep carcinogenesis through sequential cycles of mutation and clonal succession is usually described as tumor progression, or the clonal evolution of tu-mor cell populations. However, many mutations found in cancers are also compatible with normal appearing phenotypes and therefore genetic progres-sion may precede tumor progression. To better char-acterize such pretumor progression (mutations in the absence of visible phenotypic changes), a quantita-tive model was developed that postulates most onco-genic cancer mutations first accumulate in normal appearing colon crypt niche stem cells. Each crypt contains multiple stem cells, and random niche stem cell loss with replacement eventually leads to the loss of all stem cell lineages except one. This niche suc