title: K-ras mutations appear in the premalignant phase of both microsatellite stable and unstable endometrial carcinogenesis.
abstract: 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.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. gmutter@rics.bwh.harvard.edu
authors.forename: G L
authors.initials: GL
authors.lastname: Mutter
authors.forename: H
authors.initials: H
authors.lastname: Wada
authors.forename: W C
authors.initials: WC
authors.lastname: Faquin
authors.forename: T
authors.initials: T
authors.lastname: Enomoto
mesh_terms: 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*
chemical_list: D004273:DNA, Neoplasm