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Received: 11 September 2018
Accepted: 11 September 2019
Published online: 23 October 2019
The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer1. However, our understanding of the earliest phases of colorectal neoplastic changes-which may occur in morphologically normal tissue-is comparatively limited, as for most cancer types. Here we use whole-genome sequencing to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed; some of these were ubiquitous and continuous, whereas others were only found in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers exhibit substantially increased mutational burdens relative to normal cells. Sequencing normal colorectal cells provides quantitative insights into the genomic and clonal evolution of cancer.
Sequencing of the genomes of over 20,000 cancers of several types has identified the repertoire of driver mutations in cancer genes that convert normal cells into cancer cells and revealed the mutational signatures of the underlying biological processes that generate somatic mutations2,3. Cancers are, however, end stages of an evolutionary process that operates within populations of cells, and commonly arise through the accumulation of several driver mutations that engender a series of clonal expansions. Understanding this progression has depended on the identification of somatic mutations in morphologically abnormal neoplastic proliferations that represent intermediate stages between normal cells and cancer cells1.
As for most cancer types, the earliest stages of progression to colorectal cancer remain less well understood. The driver mutation that first sets a colorectal epithelial cell on the path to cancer is probably caused by mutational processes that also operate in normal cells and that we only understand to a limited extent. The nature and numbers of the earliest neoplastic clones with driver mutations-which conceivably are morphologically indistinguishable from normal cells-are similarly unclear. In large part, these deficiencies are due to the technical challenge of identifying somatic mutations in normal tissues, which are composed of myriad microscopic cell clones. Several different approaches have been adopted to...