The Landscape of Somatic Mutation in Normal Colorectal Epithelial Cells

Overview

Journal Nature

Specialty Science

Date 2019 Oct 25

PMID 31645730

Citations 328

Authors

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 ONeill

Christopher Alder

Jingwei Wang

Rebecca C Fitzgerald

Matthias Zilbauer

Nicholas Coleman

Kourosh Saeb-Parsy

Inigo Martincorena

Peter J Campbell

Michael R Stratton

Affiliations

Soon will be listed here.

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 cancer. 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.

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