p53 mutation in normal esophagus promotes multiple stages of carcinogenesis but is constrained by clonal competition

Abstract

Aging normal human epithelia, such as the esophagus, accumulate a substantial burden of TP53 mutant clones. These are the origin of most esophageal squamous carcinomas, in which biallelic TP53 disruption is almost frequent. However, the cellular mechanisms by which p53 mutants colonize the esophagus and participate in the subsequent stages of transformation are unclear. Here we show that inducing the p53R245W mutant in single esophageal progenitor cells in transgenic mice confers a proliferative advantage that drives clonal expansion but does not disrupt normal epithelial structure or function. Loss of the remaining p53 allele in mutant cells does not increase their competitive fitness, creating a bottleneck to the development of chromosomally unstable p53R245W/null epithelium. In carcinogenesis, p53 mutation does not initiate tumor formation, but tumors developing from areas with p53 mutation and LOH are larger and show extensive chromosomal instability compared to lesions arising in wild type epithelium. We conclude that p53 has distinct functions at different stages of carcinogenesis and that LOH within p53 mutant clones in normal epithelium is a critical step in malignant transformation.