Frequent clones of p53-mutated keratinocytes in normal human skin

Frequent clones of p53-mutated keratinocytes in normal human skin

Departments of ^*Therapeutic Radiology, ^§Dermatology, and ^‖Genetics, and ^‡Section of Plastic Surgery, Department of Surgery, and ^**Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT 06510; ^†Connecticut Center for Plastic Surgery, New Haven, CT 06511; and ^¶Biostatistics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20205

Abstract

The multiple genetic hit model of cancer predicts that normal individuals should have stable populations of cancer-prone, but noncancerous, mutant cells awaiting further genetic hits. We report that whole-mount preparations of human skin contain clonal patches of p53-mutated keratinocytes, arising from the dermal–epidermal junction and from hair follicles. These clones, 60–3000 cells in size, are present at frequencies exceeding 40 cells per cm² and together involve as much as 4% of the epidermis. In sun-exposed skin, clones are both more frequent and larger than in sun-shielded skin. We conclude that, in addition to being a tumorigenic mutagen, sunlight acts as a tumor promoter by favoring the clonal expansion of p53-mutated cells. These combined actions of sunlight result in normal individuals carrying a substantial burden of keratinocytes predisposed to cancer.

Footnotes

↵ ‡‡ To whom reprint requests should be addressed at: Department of Therapeutic Radiology, Yale School of Medicine, 333 Cedar Street/HRT 309, New Haven, CT 06510.
Aaron B. Lerner, Yale University School of Medicine, New Haven, CT
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