We have developed and utilised a new method for identifying genes that when mutated drive colorectal tumourigenisis. This has led us to identify numerous new cancer driver genes several of which we have investigated in more detail. These genes are mutated at low frequency in colorectal cancer suggesting that infrequently mutated genes can contribute to tumour development. The function of these genes is interesting. One of them appears to function in a similar way to other, well known cancer driver genes and is therefore likely to represent an alternative pathway for tumour initiation via this route. Another has a much different function. When mutated it leads to a reprogramming of adult intestinal tissue to a state reminiscent of the developing, fetal intestine. This reprogramming is also observed during intestinal regeneration suggesting that mutations in this gene drive cancer initiation via a different path, with similarities to tissue regeneration. A third, controls a process called cell plasticity, and, when mutated, leads to cancer progression. Together, the main results of our project support our original hypothesis that infrequently mutated genes contribute to cancer. In addition to this, by investigating in more detail, the function of these genes we are gaining a better understanding of the different ways tumours can form and spread. We believe that these findings will have important implications on our understanding of cancer driving mutations.