RAS/RAF mutation and defective DNA mismatch repair in endometrial cancers

David G. Mutch, Matthew A. Powell, Mary Ann Mallon, Paul J. Goodfellow, David M. Gershenson

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


Objective: Defective DNA mismatch repair is a common genetic abnormality in both colon cancers and endometrial cancers. Cancers with defective DNA mismatch repair have the so-called mutator phenotype and accumulate genetic errors at an increased rate. An early mutational target in cells with defect DNA mismatch repair may be the RAS/RAF pathway. Colon cancers often have KRAS2 mutations and, if not KRAS2 mutations, may have BRAF mutations. This study investigated the spectrum and frequency of mutations in BRAF and KRAS2 in endometrial carcinomas on the basis of mismatch repair status. Study design: Four hundred forty-one patients with endometrial cancer were staged properly and graded and evaluated for mismatch repair status. These patients were then stratified to groups by the degree of microsatellite instability that was observed in their tumors. One hundred forty-six of the selected tumors were then evaluated for KRAS2 and BRAF mutations on the basis of their microsatellite instability. Results: One hundred forty-six endometrioid endometrial cancers were evaluated for KRAS2 and BRAF mutations. Thirty-five cancers (24%) had activating KRAS2 mutations, but only a single BRAF mutation was identified in an microsatellite instability-positive cancer. Twenty-four of 81 microsatellite instability high cancers (29.6%) in which the MLH1 repair gene was methylated had KRAS2 mutations. When compared with the other groups, this finding approached statistical significance (P = .06). KRAS2 mutation status was associated with increasing age at diagnosis (P = .02). Conclusion: Despite many similarities between colon and endometrial cancers, the mechanism of the development of endometrial cancers appears to be different from colon cancers in that BRAF is not affected by a mismatch repair problem, because only KRAS2 mutations were seen. In addition, increasing age appears to lead to an increased likelihood that such a mutation will occur.

Original languageEnglish
Pages (from-to)935-939
Number of pages5
JournalAmerican journal of obstetrics and gynecology
Issue number4
StatePublished - Apr 2004


  • BRAF mutation
  • Colon
  • Endometrial cancer
  • KRAS2 mutation
  • Microsatellite instability


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