Gene expression analysis indicates that developmental DES exposure results in persistent altered gene expression of oestrogen-responsive genes in the uterus that may explain the increased susceptibility to tumour development.
Interestingly, the tumour suppressor PTEN is down-regulated in the majority of tumours, analogous to loss of PTEN expression in human tumours.
2000 Study Abstract
PTEN tumor suppressor gene mutations are the most frequent genetic lesions in endometrial adenocarcinomas of the endometrioid subtype. Testing the hypothesis that altered PTEN function precedes the appearance of endometrial adenocarcinoma has been difficult, however, partly because of uncertainties in precancer diagnosis.
Two series of endometrial cancer and precancer (endometrial intraepithelial neoplasia, as diagnosed by computerized morphometric analysis) tissue samples were studied, one for PTEN mutations by the use of denaturing gradient gel electrophoresis and another for PTEN protein expression by immunohistochemistry. Endometria altered by high estrogen levels that are unopposed by progestins—conditions known to increase cancer risk—were also studied by immunohistochemistry. Fisher’s exact test was used for statistical analysis.
The PTEN mutation rate was 83% (25 of 30) in endometrioid endometrial adenocarcinomas and 55% (16 of 29) in precancers, and the difference in number of mutations was statistically 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 altered by unopposed estrogens showed isolated PTEN-negative glands.
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 premalignant disease. Individual PTEN-negative glands in estrogen-exposed endometria are the earliest recognizable stage of endometrial carcinogenesis. Proliferation into dense clusters that form discrete premalignant lesions follows.
Thus, decreased PTEN expression or function is a marker of the earliest endometrial precancers, and we propose that use of PTEN immunostaining in a clinical setting may be informative in identifying premalignant lesions that are likely to progress to carcinoma.
Sources and more information
- Full text (free access) : Altered PTEN Expression as a Diagnostic Marker for the Earliest Endometrial Precancers, Journal of the National Cancer Institute, Volume 92, Issue 11, 7, Pages 924–930, doi.org/10.1093/jnci/92.11.924, 07 June 2000.
- PTEN protein in endometrial cancer and precancerous endometrial intraepithelial neoplasia featured image credit academic figure/55841967/5f2_C4TT.