Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers

Background: PTEN tumor suppressor gene mutations are the most frequent gene tic lesions in endometrial adenocarcinomas of the endometrioid subtype. Tes ting the hypothesis that altered PTEN function precedes the appearance of e ndometrial adenocarcinoma has been difficult, however, partly because of un certainties in precancer diagnosis. Methods: Two series of endometrial canc er and precancer (endometrial intraepithelial neoplasia, as diagnosed by co mputerized morphometric analysis) tissue samples were studied, one for PTEN mutations by the use of denaturing gradient gel electrophoresis and anothe r for PTEN protein expression by immunohistochemistry. Endometria altered b y high estrogen levels that are unopposed by progestins-conditions known to increase cancer risk-were also studied by immunohistochemistry, Fisher's e xact test was used for statistical analysis. Results: The PTEN mutation rat e was 83% (25 of 30) in endometrioid endometrial adenocarcinomas and 55% (1 6 of 29) in precancers, and the difference in number of mutations was stati stically significant (two-sided P = .025), No normal endometria showed PTEN mutations, Although most precancers and cancers had a mutation in only one PTEN allele, endometrioid endometrial adenocarcinomas showed complete loss of PTEN protein expression in 61% (20 of 33) of cases, and 97% (32 of 33) showed at least some diminution in expression. Cancers and most precancers exhibited contiguous groups of PTEN-negative glands, while endometria alter ed by unopposed estrogens showed isolated PTEN-negative glands. Conclusions : Loss of PTEN function by mutational or other mechanisms is an early event in endometrial tumorigenesis that may occur in response to known endocrine risk factors and offers an informative immunohistochemical biomarker for p remalignant disease, Individual PTEN-negative glands in estrogen-exposed en dometria are the earliest recognizable stage of endometrial carcinogenesis, Proliferation into dense clusters that form discrete premalignant lesions follows.