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Analysis of MSH3 in Endometrial Cancers With Defective DNA Mismatch Repair

Department of Obstetrics and Gynecology and Department of Surgery, Washington University School of Medicine, St. Louis, Missouri; Department of Obstetrics and Gynecology, Washington University School of Medicine, Box 8064, 4911 Barnes Hospital Plaza, St. Louis, MO 63110

David G. Mutch, MD

Thomas J. Herzog, MD

Janet S. Rader, MD

Lynn D. Kowalski, MD

Alla Elbendary, MD

Paul J. Goodfellow, PhD

Department of Obstetrics and Gynecology and Department of Surgery, Washington University School of Medicine, St. Louis, Missouri

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 MSH-3 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 (A) 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 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 A mutation.

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

Key Words: MSH3 • DNA mismatch repair • endometrial cancer • methylation • microsatellite instability

Journal of the Society for Gynecologic Investigation, Vol. 5, No. 4, 210-216 (1998)
DOI: 10.1177/107155769800500409


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