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PURPOSE: Microsatellite instability (MSI) is found in 10% to 15% of sporadic colorectal tumors and is usually caused by defects in DNA mismatch repair (MMR). In 1997, a panel of microsatellite markers including mononucleotide and dinucleotide repeats was recommended by a National Cancer Institute workshop on MSI. We investigated the relationship between instability of these markers and MMR protein expression in a cohort of sporadic colorectal cancer patients. EXPERIMENTAL DESIGN: Paraffin sections of normal and tumor tissue from 262 colorectal cancer patients were examined for MSI status by PCR amplification and for MMR protein expression using antibodies against hMLH1, hPMS2, hMSH2, and hMSH6. RESULTS: Twenty-six (10%) of the patients studied had tumors with a high level of MSI (MSI-H). The frequencies of MSI were the same in African-American and Caucasian patients. Each of the MSI-H tumors had mutations in both mononucleotide and dinucleotide repeats and had loss of MMR protein expression, as did two tumors that had low levels of MSI (MSI-L). These two MSI-L tumors exhibited mutations in mononucleotide repeats only, whereas eight of the other nine MSI-L tumors had mutations in just a single dinucleotide repeat. There was not a statistically significant difference in outcomes between patients whose tumors were MMR-positive or MMR-negative, although there was a slight trend toward improved survival among those with MMR-deficient tumors. CONCLUSIONS: The choice of microsatellite markers is important for MSI testing. Examination of mononucleotide repeats is sufficient for detection of tumors with MMR defects, whereas instability only in dinucleotides is characteristic of MSI-L/MMR-positive tumors.

Original publication

DOI

10.1158/1078-0432.CCR-04-0234

Type

Journal article

Journal

Clin Cancer Res

Publication Date

15/03/2005

Volume

11

Pages

2180 - 2187

Keywords

Adaptor Proteins, Signal Transducing, Adenosine Triphosphatases, Adult, African Americans, Aged, Aged, 80 and over, Base Pair Mismatch, Carrier Proteins, Cohort Studies, Colon, Colorectal Neoplasms, DNA Repair Enzymes, DNA-Binding Proteins, Female, Gene Expression Regulation, Neoplastic, Genomic Instability, Humans, Male, Microsatellite Repeats, Middle Aged, Mismatch Repair Endonuclease PMS2, MutL Protein Homolog 1, MutS Homolog 2 Protein, Neoplasm Proteins, Nuclear Proteins, Proto-Oncogene Proteins, Rectum, Sensitivity and Specificity, Whites