Identifying and functionally characterising colorectal cancer driver mutations (360G-Wellcome-214388_Z_18_Z)

The identification of cancer driver genes is central to understanding carcinogenesis and to preventing and treating cancer. In colorectal cancer (CRC) only a handful of major driver genes are established. We do not known the full complement of mutations and other molecular lesions that cause CRC, and explain its diversity, because the search for CRC drivers has focused heavily on coding regions. Despite being a major cause of cancer-related death, CRC is poorly represented in large projects including the International Cancer Genome Consortium. The availability of whole-genome sequencing (WGS) data through initiatives including the 100,000 Genomes Project (100KGP) offers the opportunity to identify different classes of functional mutations for CRC and decipher their biological impact. We shall use complementary experimental approaches to achieve these aims in a work programme comprising three phases: (1) cataloguing the mutational landscape of CRC by analysis of 100KGP, in- house and publicly accessible WGS data; (2) identifying recurrently mutated driver loci (coding, non-coding and copy number) by integrating mutation data with tissue-specific gene expression, epigenetic and topographical data; and (iii) functional analyses to validate and delineate oncogenic mechanisms. Our findings should facilitate discovery of novel therapeutic and chemoprevention agents and improve patient stratification for personalising therapy.