Stochastic fate of p53-mutant epidermal progenitor cells is tilted toward proliferation by UV B during preneoplasia.
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, higher-intensity 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.
Klein
Allon M
AM
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Brash
Douglas E
DE
Jones
Philip H
PH
Simons
Benjamin D
BD
D000818:Animals; D049109:Cell Proliferation / Q000528:radiation effects*; D000078404:Epidermal Cells; D004817:Epidermis / Q000473:pathology / Q000528:radiation effects; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009381:Neoplasms, Radiation-Induced / Q000473:pathology / Q000503:physiopathology; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D012878:Skin Neoplasms / Q000473:pathology / Q000503:physiopathology; D013234:Stem Cells / Q000166:cytology / Q000502:physiology* / Q000528:radiation effects*; D013269:Stochastic Processes; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*
D016159:Tumor Suppressor Protein p53