RT Journal Article
SR Electronic
T1 The landscape of somatic mutation in normal colorectal epithelial cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 416800
DO 10.1101/416800
A1 Henry Lee-Six
A1 Peter Ellis
A1 Robert J. Osborne
A1 Mathijs A. Sanders
A1 Luiza Moore
A1 Nikitas Georgakopoulos
A1 Franco Torrente
A1 Ayesha Noorani
A1 Martin Goddard
A1 Philip Robinson
A1 Tim H. H. Coorens
A1 Laura O’Neill
A1 Christopher Alder
A1 Jingwei Wang
A1 Rebecca C. Fitzgerald
A1 Matthias Zilbauer
A1 Nicholas Coleman
A1 Kourosh Saeb-Parsy
A1 Inigo Martincorena
A1 Peter J. Campbell
A1 Michael R. Stratton
YR 2018
UL http://biorxiv.org/content/early/2018/09/13/416800.abstract
AB The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions leading to cancer. As for most cancer types, however, understanding of the earliest phases of colorectal neoplastic change, which may occur in morphologically normal tissue, is comparatively limited because of the difficulty of detecting somatic mutations in normal cells. Each colorectal crypt is a small clone of cells derived from a single recently-existing stem cell. Here, we whole genome sequenced hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed, some ubiquitous and continuous, others only found in some individuals, in some crypts or during some phases of the cell lineage from zygote to adult cell. Likely driver mutations were present in ∼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.