The landscape of somatic mutation in normal colorectal epithelial cells

The colorectal adenoma–carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer 1 . However, our understanding of the earliest phases of colorectal neoplastic changes—which may occur in morp...

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Published in:Nature (London) Vol. 574; no. 7779; pp. 532 - 537
Main Authors: Lee-Six, Henry, Olafsson, Sigurgeir, Ellis, Peter, Osborne, Robert J., Sanders, Mathijs A., Moore, Luiza, Georgakopoulos, Nikitas, Torrente, Franco, Noorani, Ayesha, Goddard, Martin, Robinson, Philip, Coorens, Tim H. H., O’Neill, Laura, Alder, Christopher, Wang, Jingwei, Fitzgerald, Rebecca C., Zilbauer, Matthias, Coleman, Nicholas, Saeb-Parsy, Kourosh, Martincorena, Inigo, Campbell, Peter J., Stratton, Michael R.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01.10.2019
Nature Publishing Group
Subjects:
45/100
45/22
45/23
45/41
631/532/2437
631/67/1504/1885/1393
631/67/69
Adenoma - genetics
Adenoma - pathology
Aged
Axin Protein - genetics
Carcinoma - genetics
Carcinoma - pathology
Cell Transformation, Neoplastic
Clone Cells - cytology
Clone Cells - metabolism
Colon (Anatomy)
Colon - cytology
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
DNA Copy Number Variations
DNA Mutational Analysis
Epithelial cells
Epithelial Cells - cytology
Epithelial Cells - metabolism
Female
Genetic aspects
Humanities and Social Sciences
Humans
Intestinal Mucosa - cytology
Intestinal Mucosa - metabolism
Intestinal Mucosa - pathology
Male
Middle Aged
multidisciplinary
Mutation
Mutation (Biology)
Physiological aspects
Prodromal Symptoms
Rectum
Rectum - cytology
Science
Science (multidisciplinary)
Stem Cells - cytology
Stem Cells - metabolism
United Kingdom
ISSN:0028-0836, 1476-4687, 1476-4687
Online Access:Get full text
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Summary:The colorectal adenoma–carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer 1 . 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. Genome sequencing of hundreds of normal colonic crypts from 42 individuals sheds light on mutational processes and driver mutations in normal colorectal epithelial cells.
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ISSN:0028-0836
1476-4687
1476-4687
DOI:10.1038/s41586-019-1672-7