Analysis of MSH3 in endometrial cancers with defective DNA mismatch repair

Elizabeth M. Swisher, David G. Mutch, Thomas J. Herzog, Janet S. Rader, Lynn D. Kowalski, Alaa Elbendary, Paul J. Goodfellow

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19 Scopus citations


OBJECTIVE: To clarify the origin of defective mismatch repair (MMR) in sporadic endometrial cancers with microsatellite instability (MSI), a thorough mutation analysis was performed on the human mismatch repair gene MSH3. METHODS: Twenty-eight MSI-positive endometrial cancers were investigated for mutations in the human mismatch repair gene MSH3 using single-strand conformation variant (SSCV) analysis of all 24 exons. All variants were sequenced. Loss of heterozygosity was investigated at all MSH3 polymorphisms discovered. A subset of tumors were investigated for methylation of the 5' promoter region of MSH3 using Southern blot hybridization. RESULTS: An identical single-base deletion (ΔA) predicted to result in a truncated protein was discovered in six tumors (21.4%). This deletion occurs in a string of eight consecutive adenosine residues (A8). Because simple repeat sequences are unstable in cells with defective MMR, the observed mutation may be an effect, rather than a cause, of MSI. Evidence of inactivation of the second MSH3 allele in tumors with the ΔA mutation would strongly, support a causal role for these MSH3 mutations. However, there was no evidence of a second mutation, loss of sequences, or methylation of the promoter region in any of the tumors with the ΔA mutation. CONCLUSION: Although the ΔA mutation is a frequent event in sporadic MSI-positive endometrial cancers, it may not be causally associated with defective DNA MMR.

Original languageEnglish
Pages (from-to)210-216
Number of pages7
JournalJournal of the Society for Gynecologic Investigation
Issue number4
StatePublished - Jul 1 1998


  • DNA mismatch repair
  • Endometrial cancer
  • MSH3
  • Methylation
  • Microsatellite instability


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