American Association for Cancer Research
21598290cd201092-sup-248092_3_supp_6645816_qq5rqf.pdf (3.19 MB)

Supplementary Data from Selection of Oncogenic Mutant Clones in Normal Human Skin Varies with Body Site

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journal contribution
posted on 2023-04-03, 22:44 authored by Joanna C. Fowler, Charlotte King, Christopher Bryant, Michael W.J. Hall, Roshan Sood, Swee Hoe Ong, Eleanor Earp, David Fernandez-Antoran, Jonas Koeppel, Stefan C. Dentro, David Shorthouse, Amer Durrani, Kate Fife, Edward Rytina, Doreen Milne, Amit Roshan, Krishnaa Mahububani, Kourosh Saeb-Parsy, Benjamin A. Hall, Moritz Gerstung, Philip H. Jones

Supplementary Figures S1-S7 and Tables S1 and S2


Wellcome Trust

Wellcome Sanger Institute

Cancer Research UK

Medical Research Council

Royal Society



Skin cancer risk varies substantially across the body, yet how this relates to the mutations found in normal skin is unknown. Here we mapped mutant clones in skin from high- and low-risk sites. The density of mutations varied by location. The prevalence of NOTCH1 and FAT1 mutations in forearm, trunk, and leg skin was similar to that in keratinocyte cancers. Most mutations were caused by ultraviolet light, but mutational signature analysis suggested differences in DNA-repair processes between sites. Eleven mutant genes were under positive selection, with TP53 preferentially selected in the head and FAT1 in the leg. Fine-scale mapping revealed 10% of clones had copy-number alterations. Analysis of hair follicles showed mutations in the upper follicle resembled adjacent skin, but the lower follicle was sparsely mutated. Normal skin is a dense patchwork of mutant clones arising from competitive selection that varies by location. Mapping mutant clones across the body reveals normal skin is a dense patchwork of mutant cells. The variation in cancer risk between sites substantially exceeds that in mutant clone density. More generally, mutant genes cannot be assigned as cancer drivers until their prevalence in normal tissue is known.See related commentary by De Dominici and DeGregori, p. 227.This article is highlighted in the In This Issue feature, p. 211

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