Improved Detection of Microsatellite Instability in Early Colorectal Lesions

Abstract

Microsatellite instability (MSI) occurs in over 90% of Lynch syndrome cancers and is considered a hallmark of the disease. MSI is an early event in colon tumor development, but screening polyps for MSI remains controversial because of reduced sensitivity compared to more advanced neoplasms. To increase sensitivity, we investigated the use of a novel type of marker consisting of long mononucleotide repeat (LMR) tracts. Adenomas from 160 patients, ranging in age from 29–55 years old, were screened for MSI using the new markers and compared with current marker panels and immunohistochemistry standards. Overall, 15 tumors were scored as MSI-High using the LMRs compared to 9 for the NCI panel and 8 for the MSI Analysis System (Promega). This difference represents at least a 1.7-fold increase in detection of MSI-High lesions over currently available markers. Moreover, the number of MSI-positive markers per sample and the size of allelic changes were significantly greater with the LMRs (p = 0.001), which increased confidence in MSI classification. The overall sensitivity and specificity of the LMR panel for detection of mismatch repair deficient lesions were 100% and 96%, respectively. In comparison, the sensitivity and specificity of the MSI Analysis System were 67% and 100%; and for the NCI panel, 75% and 97%. The difference in sensitivity between the LMR panel and the other panels was statistically significant (p<0.001). The increased sensitivity for detection of MSI-High phenotype in early colorectal lesions with the new LMR markers indicates that MSI screening for the early detection of Lynch syndrome might be feasible.

Subclonal diversity arises early even in small colorectal tumours and contributes to differential growth fates

“…20 Without matching normal tissue samples, tumour only samples were classified as MSI-High (MSI-H) that had three or more alleles per marker, as this is a rare event in normal cells, in at least two of the five markers in the panel.…”

DNA Mismatch Repair Deficiency Detection in Colorectal Cancer by a New Microsatellite Instability Analysis System

“…The frequency of mutation in mononucleotide repeats increases exponentially with accumulating number of repeating units, which leads to increased sensitivity of MSI detection. Their study showed that employing the long mononucleotide repeat markers improved detection sensitivity and specificity compared with the commercially available five mononucleotide repeat panel and NCI panel in early colorectal lesions and other tumors [15].…”

Distribution of Somatic Mutations of Cancer-Related Genes According to Microsatellite Instability Status in Korean Gastric Cancer

“…Allelic sizes to match the tumor and normal samples were compared and considered to be MSI unstable if there was a shift of 3 bp or more in the tumor allele. [29] All tumors with 1 or more unstable markers were regarded as carrying some degree of instability and were defined as MSI and MS stable (MSS) when there were no unstable markers. The cutoff for classification was applied on the basis of the threshold of about 40% that is commonly used to discriminate MSI-H (high) and MSI-L (low) tumors.…”