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. 1996 Nov 26;93(24):14025-9.
doi: 10.1073/pnas.93.24.14025.

Frequent clones of p53-mutated keratinocytes in normal human skin

A S Jonason  1 , S Kunala, G J Price, R J Restifo, H M Spinelli, J A Persing, D J Leffell, R E Tarone, D E Brash
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Frequent clones of p53-mutated keratinocytes in normal human skin

A S Jonason et al. Proc Natl Acad Sci U S A. .

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.

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Figures

Figure 1
Figure 1
p53-immunopositive clones in whole-mount preparations of human epidermis. Clones arising from (A) the dermal–epidermal junction and (B) a hair follicle. In both cases, view is from the basal surface to show follicles. (×100.)
Figure 2
Figure 2
Increase of clone frequency with sun exposure. Histogram shows the average frequency of p53-mutated patches from sun-shielded, intermittently exposed, and chronically sun-exposed skin. Mean patch frequency for intermittently exposed skin excludes the outlier. Bars represent SEM.
Figure 3
Figure 3
Conical clone of p53-mutated keratinocytes. Shown is the side view of a three-dimensionally reconstructed immunofluorescent cone from an epidermal whole mount. Opacity of the surrounding background epidermis has been adjusted to allow complete false-color visualization of all immunostaining cells in the z-scan. The cone’s apex lies at the bottom of the view, along the plane of the basal surface. Confocal images were captured using a Bio-Rad MRC 600 laser scanning confocal microscope with ×20 objective.
Figure 4
Figure 4
Increase of clone size with sun exposure. Dot histogram shows the area in mm2 of individual p53-mutated patches from sun-shielded, intermittently exposed, and chronically sun-exposed skin. Each point represents an individual clone.
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