Progression model. A colon consists of ~15 million epithelial clonal units called crypts. Each crypt contains ~2,000 cells and is maintained by a smaller number of stem cells that are present near its base. A cancer genealogy starts at the zygote and ends when the present day cancer cell is detected. The predominant phenotype in this genealogy is a stem cell phenotype because visible tumors are rare before the age of 50 years. Many colorectal crypt stem cells (m × N) are produced early in life, and these lineages in different crypts independently divide and accumulate passenger (gray arrows) and driver (blue arrows) somatic mutations with aging. Transformation occurs by chance when an appropriate combination of k rate-limiting driver pathway mutations first accumulates in a single stem cell lineage.