K-ras mutations appear in the premalignant phase of both microsatellite stable and unstable endometrial carcinogenesis.
OBJECTIVE
Sequential events of endometrial tumorigenesis can be studied by comparison of genetic lesions seen in normal, premalignant, and malignant tissues. The distribution of k-ras mutations in microsatellite stable and unstable premalignant lesions was studied to determine whether this gene is implicated in both tumorigenic pathways.


METHODS
K-ras mutations were analysed by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and direct sequencing in matched endometrial normal, premalignant (atypical hyperplasias), and adenocarcinoma 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 molecular testing (non-random X inactivation or clonal altered microsatellites) for an expected feature of precancers--that is, monoclonality.


RESULTS
Equivalent K-ras mutation frequencies were seen in microsatellite stable (six of 33) and unstable (three of 23) cancers. In both types, K-ras mutation in monoclonal precancers usually corresponded to a change from normal to an equivocal (two of 12) or hyperplastic (10 of 12) histology. Divergent K-ras genotypes among multiple neoplastic tissues of individual patients (two of six patients) are exceptions explained either by multicentric premalignant disease, or acquisition of K-ras mutation late in neoplastic progression.


CONCLUSIONS
K-ras mutation occurs in both premalignant microsatellite stable and unstable endometrial neoplasia, sometimes before acquisition of features readily diagnostic as atypical endometrial hyperplasia.
Mutter
G L
GL
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. gmutter@rics.bwh.harvard.edu
Wada
H
H
Faquin
W C
WC
Enomoto
T
T
D000230:Adenocarcinoma / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004714:Endometrial Hyperplasia / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D011905:Genes, ras; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation; D011230:Precancerous Conditions / Q000235:genetics*
D004273:DNA, Neoplasm