WGS___Mutant_clone_mapping_in_normal_oesohagus_and_skin

We will use whole genome sequencing to examine normal appearing oesophageal epithelium and skin to determine the mutational burden. DNA will be extracted from epithelia of a defined size and we will overlay positional information from the epithelial pieces to give clone maps over a wide area. This will be done in both oesophageal epithelium and skin

Type: Cancer Genomics
Archiver: European Genome-Phenome Archive (EGA)

2 Datasets 4 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001004159	The extent to which cells in normal tissues accumulate mutations during life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant clones in normal esophageal epithelium from nine donors aged 20-75. Somatic mutations accumulate with age and are mainly caused by intrinsic mutational processes. We found strong Darwinian selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of such clones per square centimeter. By middle age, clones with cancer-associated mutations cover most of the epithelium, with NOTCH1 and TP53 mutations affecting 40% and 10% of all cells, respectively. Remarkably, the prevalence of NOTCH1 mutations in normal esophagus is several times higher than in esophageal cancers. The esophagus emerges as an evolving patchwork of mutant clones that colonize the majority of the epithelium, with implications for our understanding of cancer and ageing.	HiSeq X Ten	25
EGAD00001006194	The risk of getting non-melanoma skin cancer varies over 40-fold across the body. Here we map mutations in normal skin in high and low risk sites in normal donors and those with an increased risk of skin cancer. The density of mutations varied widely, with evidence of positive and negative genetic selection. Regional differences in mutational signatures in high and low cancer risk sites and preferential selection of mutants of TP53 in high risk skin and FAT1 in lower risk skin were observed. 10% of clones had copy number changes in cancer associated genes and the largest had multiple driver mutations with loss of heterozygosity. In hair follicles, a proposed site of origin of skin cancers, mutations in the upper follicle resembled adjacent skin, but the lower follicle was sparsely mutated. We conclude cancer risk reflects the efficiency of transformation of oncogenic mutants rather than the density of mutant clones.	HiSeq X Ten Illumina HiSeq 2500 Illumina NovaSeq 6000	805

Publications	Citations
Somatic mutant clones colonize the human esophagus with age. Martincorena I, Fowler JC, Wabik A, Lawson ARJ, Abascal F, Hall MWJ, Cagan A, Murai K, Mahbubani K, Stratton MR, Fitzgerald RC, Handford PA, Campbell PJ, Saeb-Parsy K, Jones PH. Science 362: 2018 911-917	457
Measuring the distribution of fitness effects in somatic evolution by combining clonal dynamics with dN/dS ratios. Williams MJ, Zapata L, Werner B, Barnes CP, Sottoriva A, Graham TA. Elife 9: 2020 e48714	15
Selection of Oncogenic Mutant Clones in Normal Human Skin Varies with Body Site. Fowler JC, King C, Bryant C, Hall MWJ, Sood R, Ong SH, Earp E, Fernandez-Antoran D, Koeppel J, Dentro SC, Shorthouse D, Durrani A, Fife K, Rytina E, Milne D, Roshan A, Mahububani K, Saeb-Parsy K, Hall BA, Gerstung M, Jones PH. Cancer Discov 11: 2021 340-361	43
Measures of genetic diversification in somatic tissues at bulk and single-cell resolution. Moeller ME, Mon Père NV, Werner B, Huang W. Elife 12: 2024 RP89780	1