The landscape of somatic mutation in normal colorectal epithelial cells

Henry Lee-Six, Sigurgeir Olafsson, Peter Ellis, Robert J. Osborne, Mathijs A. Sanders, Luiza Moore, Nikitas Georgakopoulos, Franco Torrente, Ayesha Noorani, Martin Goddard, Philip Robinson, Tim H. H. Coorens, Laura O’Neill, Christopher Alder, Jingwei Wang, Rebecca C. Fitzgerald, Matthias Zilbauer, Nicholas Coleman, Kourosh Saeb-Parsy, Inigo Martincorena, Peter J. Campbell and Michael R. Stratton ()
Additional contact information
Henry Lee-Six: Wellcome Sanger Institute
Sigurgeir Olafsson: Wellcome Sanger Institute
Peter Ellis: Wellcome Sanger Institute
Robert J. Osborne: Wellcome Sanger Institute
Mathijs A. Sanders: Wellcome Sanger Institute
Luiza Moore: Wellcome Sanger Institute
Nikitas Georgakopoulos: University of Cambridge
Franco Torrente: Addenbrooke’s Hospital
Ayesha Noorani: University of Cambridge
Martin Goddard: Papworth Hospital NHS Trust
Philip Robinson: Wellcome Sanger Institute
Tim H. H. Coorens: Wellcome Sanger Institute
Laura O’Neill: Wellcome Sanger Institute
Christopher Alder: Wellcome Sanger Institute
Jingwei Wang: Wellcome Sanger Institute
Rebecca C. Fitzgerald: University of Cambridge
Matthias Zilbauer: Addenbrooke’s Hospital
Nicholas Coleman: Cambridge University Hospitals NHS Foundation Trust
Kourosh Saeb-Parsy: University of Cambridge
Inigo Martincorena: Wellcome Sanger Institute
Peter J. Campbell: Wellcome Sanger Institute
Michael R. Stratton: Wellcome Sanger Institute

Nature, 2019, vol. 574, issue 7779, 532-537

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-019-1672-7

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