Em. Swisher et al., ANALYSIS OF MSH3 IN ENDOMETRIAL CANCERS WITH DEFECTIVE-DNA MISMATCH REPAIR, Journal of the Society for Gynecologic Investigation, 5(4), 1998, pp. 210-216
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 wer
e investigated for mutations in the human mismatch repair gene MSH3 us
ing 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 investi
gated for methylation of the 5' promotor region of MSH3 using Southern
blot hybridization. RESULTS: An identical single-base deletion (Delta
A) predicted to result in a truncated protein was discovered in six t
umors (21.4%). This deletion occurs in a string of eight consecutive a
denosine residues (A(8)). 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 MS
H3 allele in tumours with the Delta A mutation would strongly support
a casual role for these MSH3 mutations. However, there was no evidence
of a second mutation, loss of sequences, or methylation of the promot
er region in any of the tumors with the Delta A mutation. CONCLUSION:
Although Delta A mutation is a frequent event in sporadic MSI-positive
endometrial cancers, it may not be casually associated with defective
DNA MMR. (J Soc Gynecol Invest 1998; 5:210-216). Copyright (C) 1998 b
y the Society for Gynecologic Investigation.