Our model of colorectal cancer evolution.

<p>First, founder alterations containing a set of drive alterations are accumulated in the genome and epigenome as a result of aging. After establishment of a parental clone, extensive ITH is generated by neutral evolution, although a few driver alterations are acquired as progressor alterations. Note that this illustration is based on the evolutionary tree of case 3 (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005778#pgen.1005778.g002" target="_blank">Fig 2</a>). However, an actual tumor should harbor numerous subclones, as suggested by the local ITH data (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005778#pgen.1005778.g005" target="_blank">Fig 5D</a>) and simulated single-cell mutation profile (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005778#pgen.1005778.g005" target="_blank">Fig 5B</a>).