Fowler, JC;
King, C;
Bryant, C;
Hall, MWJ;
Sood, R;
Ong, SH;
Earp, E;
... Jones, PH; + view all
(2021)
Selection of Oncogenic Mutant Clones in Normal Human Skin Varies with Body Site.
Cancer Discovery
, 11
(2)
pp. 340-361.
10.1158/2159-8290.CD-20-1092.
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Abstract
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. / Significance: 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.
| Type: | Article |
|---|---|
| Title: | Selection of Oncogenic Mutant Clones in Normal Human Skin Varies with Body Site |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1158/2159-8290.CD-20-1092 |
| Publisher version: | https://doi.org/10.1158/2159-8290.CD-20-1092 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Med Phys and Biomedical Eng |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10120558 |
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