Colorectal carcinoma (CRC) is a common cause of mortality¹, but a comprehensive description of its genomic landscape is lacking^{2,3,4,5,6,7,8,9}. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichia coli^pks+ colibactin in rectal cancers¹⁰ and the importance of the SBS93 signature^11,12,13, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations¹⁴ are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care.

结直肠癌 (CRC) 是一种常见的死亡原因¹ ，但缺乏对其基因组景观的全面描述^{2,3,4,5,6,7,8,9} 。在这里，我们对来自英国 100,000 基因组计划参与者的 2,023 个 CRC 样本进行全基因组测序，从而提供了这种癌症的高度详细的体细胞突变情况。综合分析确定了超过 250 个假定的 CRC 驱动基因，其中许多以前与 CRC 或其他癌症无关，包括编码基因组之外的几个反复出现的变化。我们扩展了 CRC 发展所涉及的分子途径，根据基因组特征定义了微卫星稳定 CRC 的四个新的常见亚组，并表明这些组具有独立的预后关联。我们还描述了几个罕见的分子 CRC 亚组，其中一些具有潜在的临床相关性，包括同时具有微卫星和染色体不稳定的癌症。我们展示了整个结直肠的一系列突变谱，这反映了病因学差异。其中包括大肠杆菌^pks+ colibactin在直肠癌中的作用¹⁰以及 SBS93 特征的重要性^11,12,13 ，这表明饮食或吸烟是一个危险因素。免疫逃逸驱动突变¹⁴在超突变肿瘤中几乎无处不在，并且发生在大约一半的微卫星稳定 CRC 中，通常以 HLA 拷贝数变化的形式出现。许多驱动突变都是可操作的，包括与罕见亚组（例如BRCA1和IDH1 ）相关的突变，凸显了全基因组测序在优化患者护理方面的作用。