Analysis of MSH3 in endometrial cancers with defective DNA mismatch repair

J Soc Gynecol Investig. 1998 Jul-Aug;5(4):210-6. doi: 10.1016/s1071-5576(98)00016-1.


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 (delta A) predicted to result in a truncated proteins 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 delta A 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 delta A mutation.

Conclusion: Although the delta A mutation is a frequent event in sporadic MSI-positive endometrial cancers, it may not be causally associated with defective DNA MMR.

MeSH terms

  • Blotting, Southern
  • DNA Methylation
  • DNA Mutational Analysis
  • DNA Repair / genetics*
  • Endometrial Neoplasms / genetics*
  • Female
  • Humans
  • Loss of Heterozygosity
  • Microsatellite Repeats
  • Polymorphism, Single-Stranded Conformational
  • Promoter Regions, Genetic
  • Restriction Mapping