BACKGROUND.
Prenatal exposure to the synthetic estrogen diethylstilbestrol (DES) is associated with the subsequent development of clear cell adenocarcinoma of the lower reproductive tract in young women, and data concerning the molecular genetic alterations involved in the etiology of this tumor type have not previously been reported. Such knowledge would be of potential value by providing insight into the molecular mechanisms of hormonal carcinogenesis in general, as well as by suggesting molecular markers for risk assessment in the estrogen-exposed population.
METHODS.
A total of 24 samples of clear cell adenocarcinoma of the vagina or cervix, 16 associated with exposure in utero to DES and 8 with no history of DES exposure, were obtained as archival fixed and embedded tissue specimens. DNA was purified from these tissues and used to examine a number of biologically plausible molecular genetic endpoints for tumor specific alterations.
RESULTS.
No evidence was found for mutations in the K -m s or H-rus protooncogenes, the Wilms' tumor (WT1) tumor suppressor gene, or the estrogen receptor gene. Sporadic overexpression of the ,053 tumor suppressor gene was detected in some tumor cell nuclei by inimunohistochemistry, but in the absence of detectable ~753 gene mutation. Genetic instability as manifested by somatic mutation of niicrosatellite repeats was widespread in these tumors, with evidence of microsatellite instability in all DES-associated tumors examined, and in 50% of those tumors not associated with DES exposure.
CONCLUSIONS. These data are consistent with the hypothesis that the induction of genoniic instability may be an important mechanism of DES-induced carcinogenesis. Cancer 1996