Mutant_clone_mapping_in_normal_oesohagus_and_skin - EGA European Genome-Phenome Archive

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Dataset ID	Description	Technology	Samples
EGAD00001004158	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.	Illumina HiSeq 2500	-
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
EGAD00001006969	NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age, but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations may promote clonal expansion but impede carcinogenesis. Here we test this hypothesis. Visualizing and sequencing NOTCH1 mutant clones in aging normal human esophagus, reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild type cells, an effect enhanced by loss of the second allele. Notch1 loss alters transcription but has minimal effects on epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. We conclude that Notch1 mutations in normal epithelium are beneficial as wild type Notch1 promotes tumor expansion. NOTCH1 blockade has therapeutic potential in esophageal squamous tumors.	Illumina HiSeq 2500	-

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	460
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
Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth. Abby E, Dentro SC, Hall MWJ, Fowler JC, Ong SH, Sood R, Herms A, Piedrafita G, Abnizova I, Siebel CW, Gerstung M, Hall BA, Jones PH. Nat Genet 55: 2023 232-245	14
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