Whole genome sequencing of 2,023 colorectal cancers reveals mutational landscapes, new driver genes and immune interactions
biorxiv(2022)
摘要
To 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 loc i ). Non-coding drivers included intronic neo-splice site alterations in APC and SMAD4 . 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 of PIK3R1 and PWRN1 , as well as amplification of CCND3 and NEDD9 . Putative driver structural variants included BRD4 and SOX9 regulatory elements, and ACVR2A and ANKRD11 hotspot deletions. The frequencies of many driver mutations, including somatic Wnt and Ras pathway variants, showed a gradient along the colorectum. The Pks-pathogenic E. coli signature and TP53 mutations 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.
### Competing Interest Statement
The authors have declared no competing interest.
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关键词
colorectal cancers,new driver genes,genome,mutational landscapes
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