Whole genome sequencing of 2,023 colorectal cancers reveals mutational landscapes, new driver genes and immune interactions

Abstract

ABSTRACTTo characterise the somatic alterations in colorectal cancer (CRC), we conducted whole-genome sequencing analysis of 2,023 tumours. We provide the most detailed high-resolution map to date of somatic mutations in CRC, and demonstrate associations with clinicopathological features, in particular location in the large bowel. We refined the mutational processes and signatures acting in colorectal tumorigenesis. In analyses across the sample set or restricted to molecular subtypes, we identified 185 CRC driver genes, of which 117 were previously unreported. New drivers acted in various molecular pathways, including Wnt (CTNND1, AXIN1, TCF3), TGF-β/BMP (TGFBR1) and MAP kinase (RASGRF1, RASA1, RAF1, and several MAP2K and MAP3K loci). Non-coding drivers included intronic neo-splice site alterations inAPCandSMAD4. Whilst there was evidence of an excess of mutations in functionally active regions of the non-coding genome, no specific drivers were called with high confidence. Novel recurrent copy number changes included deletions ofPIK3R1andPWRN1, as well as amplification ofCCND3andNEDD9. Putative driver structural variants includedBRD4andSOX9regulatory elements, andACVR2AandANKRD11hotspot deletions. The frequencies of many driver mutations, including somatic Wnt and Ras pathway variants, showed a gradient along the colorectum. The Pks-pathogenicE. colisignature andTP53mutations were primarily associated with rectal cancer. A set of unreported immune escape driver genes was found, primarily in hypermutated CRCs, most of which showed evidence of genetic evasion of the anti-cancer immune response. About 25% of cancers had a potentially actionable mutation for a known therapy. Thirty-three of the new driver genes were predicted to be essential, 17 possessed a druggable structure, and nine had a bioactive compound available. Our findings provide further insight into the genetics and biology of CRC, especially tumour subtypes defined by genomic instability or clinicopathological features.