Final Report Summary - EVOCAN (Why do cancers occur where they do? A genetic and evolutionary approach.)
EVOCAN sought to understand several aspects of cancer evolution through statistical analysis of human cancer genomes, mathematical modelling of tumorigenesis and new mouse models. Achievements can be summarised as follows: (i) Identification of pathogenic germline mutations in the DNA repair genes MBD4; (ii) explanations for tissue specificity in patients with inherited DNA repair defects, using samples from patients with inherited defects in DNA polymerase proofreading; (iii) explanation for atypical BRAF and Ras pathway mutations in colorectal cancer; (iv) identification of a methylator phenotype caused by mini-driver isocitrate dehydrogenase mutations in colorectal cancer; (v) demonstration that multiple Wnt pathway major driver and mini-driver mutations occur in colorectal cancers; and (vi) mathematical models of tumorigenesis, showing the potentially profound negative effects of a non-constant microenvironment on tumour growth. We plan to take forward several of the above projects using other funding sources. We also have legacy resources for the wider scientific community, including 8 new mouse models of cancer.