Stochastic fate ofp53-mutant epidermal progenitor cells is tilted toward proliferation by UV B during preneoplasia

Abstract

UV B (UVB) radiation induces clones of cells mutant for the p53 tumor suppressor gene in human and murine epidermis. Here we reanalyze large datasets that report the fate of clones in mice subjected to a course of UVB radiation, to uncover how p53 mutation affects epidermal progenitor cell behavior. We show that p53 mutation leads to exponential growth of clones in UV-irradiated epidermis; this finding is also consistent with the size distribution of p53 mutant clones in human epidermis. Analysis of the tail of the size distribution further reveals that the fate of individual mutant cells is stochastic. Finally, the data suggest that ending UVB exposure results in the p53 mutant cells adopting the balanced fate of wild-type cells: the loss of mutant cells is balanced by proliferation so that the population of preneoplastic cells remains constant. We conclude that preneoplastic clones do not derive from long-lived, self-renewing mutant stem cells but rather from mutant progenitors with random cell fate. It follows that ongoing, low-intensity UVB radiation will increase the number of precancerous cells dramatically compared with sporadic, higherintensity exposure at the same cumulative dose, which may explain why nonmelanoma skin cancer incidence depends more strongly on age than on radiation dosage. Our approach may be applied to determine cell growth rates in clonally labeled material from a wide range of tissues including human samples.cancer | stem cells | stochastic fate

Extensive genetic variation in somatic human tissues

“…To detect these events, they must be present in a substantial fraction of the parenchymal cells. In proliferating tissues, such as in the cases of p53 mutations in UV-irradiated skin (32) and some of the CNVs seen in normal blood cells (14), it seems probable that the somatic mutation conferred a growth advantage to the affected cells. In organs that undergo little or no proliferation in the adult, one possibility is that the observed CNV may have given a growth or differentiation advantage to the affected precursor cells during development.…”

Deep sequencing as a probe of normal stem cell fate and preneoplasia in human epidermis

“…If all point mutations conferred the same proliferative advantage, the first incomplete moment would also acquire an exponential size dependence, μ 1 ðn, tÞ ≈ e −n=NðtÞ , with NðtÞ = e νt and ν defining the net proliferative expansion rate of mutant progenitors (36). However, because such a size dependence would require all point mutations (synonymous and nonsynonymous) to confer precisely the same proliferative advantage, its relevance to the current 2 NOTCH2 NOTCH2 SALL1 SALL1 APOB SCN1A ERBB4 ERBB4 SPHKAP SPHKAP ADAM29 FAT4 FAT1 NSD1 FAT1 BAI3 BAI3 NOTCH1 NOTCH1 NOTCH1 study is unlikely.…”

Mutation, clonal fitness and field change in epithelial carcinogenesis

“…This may operate once cells become crowded, as restricting the contact area of keratinocytes with the underlying basement membrane promotes their differentiation. Similar cell crowding linked with slowing clonal expansion is seen in Tp53 mutant clones in human sun-exposed epidermis once they reach more than a thousand cells in size [39,41].…”

“…Repeated exposure of mice to low doses of UV light, below the level which causes sunburn, generates similar immunoreactive Tp53 mutant clones in the epidermis [39,40]. A reanalysis of the size distribution of clones in both mouse and human epidermis argues that UV light drives the exponential expansion of TP53 mutant clones by increasing the probability of symmetric divisions generating two progenitor cells [41,42]. On cessation of UV exposure, the clones return to homeostatic behaviour, with some clones being lost through differentiation but the persisting clones expanding, so that the proportion of mutant cells is maintained.…”

“…The mutant cell population will self-maintain over the winter, when there is little UV exposure, and expand during the summer, perhaps explaining the supralinear relationship between non-melanoma skin cancer incidence and life time UV dose, as cancer risk is dependent on the proportion of TP53 mutant cells [43,44]. Use of sunblock should thus be lifelong, as the proportionate reduction in risk will increase with age [41].…”