MOLECULAR-GENETIC ANALYSIS OF CLEAR-CELL ADENOCARCINOMAS OF THE VAGINA AND CERVIX ASSOCIATED AND UNASSOCIATED WITH DIETHYLSTILBESTROL EXPOSURE IN-UTERO

BACKGROUND. Prenatal exposure to the synthetic estrogen diethylstilbes trol (DES) is associated with the subsequent development of clear cell adenocarcinoma of the lower reproductive tract in young women, and da ta concerning the molecular genetic alterations involved in the etiolo gy of this tumor type have not previously been reported. Such knowledg e would be of potential value by providing insight into the molecular mechanisms of hormonal carcinogenesis in general, as well as by sugges ting molecular markers for risk assessment in the estrogen-exposed pop ulation. METHODS. A total of 24 samples of clear cell adenocarcinoma o f the vagina or cervix, 16 associated with exposure in utero to DES an d 8 with no history of DES exposure, were obtained as archival fixed a nd embedded tissue specimens. DNA was purified from these tissues and used to examine a number of biologically plausible molecular genetic e ndpoints for tumor specific alterations. RESULTS. No evidence was foun d for mutations in the K-ras or H-ras protooncogenes, the Wilms' tumor (WT1) tumor suppressor gene, or the estrogen receptor gene. Sporadic overexpression of the p53 tumor suppressor gene was detected in some t umor cell nuclei by immunohistochemistry, but in the absence of detect able p53 gene mutation. Genetic instability as manifested by somatic m utation of microsatellite repeats was widespread in these tumors, with evidence of microsatellite instability in all DES-associated tumors e xamined, and in 50% of those tumors not associated with DES exposure. CONCLUSIONS. These data are consistent with the hypothesis that the in duction of genomic instability may be an important mechanism of DES-in duced carcinogenesis. (C) American Cancer Society.