Molecular identification of latent precancers in histologically normal endometrium

Discovery of somatically mutated cells in human tissues has been less frequent than would be predicted by in vitro mutational rates. We analyzed the PTEN tumor suppressor gene as an early marker for endometrial carcinogenesis, and we show that 43% of histologically normal premenopausal endometria contain rare glands that fail to express PTEN protein because of mutation and/or deletion. These persist between menstrual cycles. Histopathology of PTEN-null glands is initially unremarkable, but with progression, they form distinctive high-density clusters. These data are consistent with a progression model in which initial mutation is not rate limiting.