K-ras mutations appear in the premalignant phase of both microsatellite stable and unstable endometrial carcinogenesis

Aims-Sequential events of endometrial tumorigenesis can be studied by compa rison of genetic lesions seen in normal, premalignant, and malignant tissue s. The distribution of k-ras mutations in microsatellite stable and unstabl e premalignant lesions was studied to determine whether this gene is implic ated in both tumorigenic pathways. Methods-K-ras mutations were analysed by polymerase chain reaction-single s trand conformation polymorphism (PCR-SSCP) and direct sequencing in matched endometrial normal, premalignant (atypical hyperplasias), and adenocarcino ma tissues from individual patients. Identification of precancers solely by their appearance as atypical endometrial hyperplasias is very subjective; therefore, in addition to histopathological assessment, we performed molecu lar testing (non-random X inactivation or clonal altered microsatellites) f or an expected feature of precancers that is, monoclonality. Results-Equivalent K-ras mutation frequencies were seen in microsatellite s table (six of 33) and unstable (three of 23) cancers. In both types, K-ras mutation in monoclonal precancers usually corresponded to a change from nor mal to an equivocal (two of 12) or hyperplastic (10 of 12) histology. Diver gent K-ras genotypes among multiple neoplastic tissues of individual patien ts (two of six patients) are exceptions explained either by multicentric pr emalignant disease, or acquisition of K-ras mutation late in neoplastic pro gression. Conclusions-K-ras mutation occurs in both premalignant microsatellite stabl e and unstable endometrial neoplasia, sometimes before acquisition of featu res readily diagnostic as atypical endometrial hyperplasia.