Allelic losses and DNA methylation at DNA mismatch repair loci in sporadic colorectal cancer.
Normal and tumor DNA samples of 35 patients with sporadic colorectal carcinoma were analyzed for microsatellite alterations at 12 markers linked to mismatch repair loci: hMLH1, hMSH2, hMSH3, hMSH6, hPMS1 and hPMS2. Remarkably, no correlation was observed between the replication error phenotype (RER+) and allelic losses at these loci. Hemizygous deletions, seen in 6/35 (17%) informative cases at hMLH1, 4/27 (15%) at hMSH2/hMSH6 and 6/34 (18%) at hMSH3, were rarely found in RER+ tumors. Since mismatch repair protein components act in molecular complexes of defined stoichiometry we propose that hemizygous deletion of the corresponding loci may be involved in colorectal tumorigenesis through defects in cellular functions other than replication error correction. The analysis of the methylation status of the promoter region of hMLH1 revealed that methylation might be an important mechanism of this locus inactivation in RER+ sporadic colorectal cancer.
Benachenhou
N
N
Division of Hemato-Oncology, Charles Bruneau Cancer Center, Sainte-Justine Hospital, Montréal, Québec, Canada.
Guiral
S
S
Gorska-Flipot
I
I
Michalski
R
R
Labuda
D
D
Sinnett
D
D
D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases; D002352:Carrier Proteins; D002874:Chromosome Mapping; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D005656:Fungal Proteins / Q000235:genetics; D006801:Humans; D019656:Loss of Heterozygosity; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D011506:Proteins / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C088996:PMS1 protein, human; D011506:Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D045643:DNA Repair Enzymes