TY - JOUR
T1 - Analysis of MSH3 in endometrial cancers with defective DNA mismatch repair
AU - Swisher, Elizabeth M.
AU - Mutch, David G.
AU - Herzog, Thomas J.
AU - Rader, Janet S.
AU - Kowalski, Lynn D.
AU - Elbendary, Alaa
AU - Goodfellow, Paul J.
PY - 1998/7/1
Y1 - 1998/7/1
N2 - 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.
AB - 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.
KW - DNA mismatch repair
KW - Endometrial cancer
KW - MSH3
KW - Methylation
KW - Microsatellite instability
UR - http://www.scopus.com/inward/record.url?scp=0031823235&partnerID=8YFLogxK
U2 - 10.1016/S1071-5576(98)00016-1
DO - 10.1016/S1071-5576(98)00016-1
M3 - Article
C2 - 9699180
AN - SCOPUS:0031823235
SN - 1071-5576
VL - 5
SP - 210
EP - 216
JO - Journal of the Society for Gynecologic Investigation
JF - Journal of the Society for Gynecologic Investigation
IS - 4
ER -