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Improved Detection of Microsatellite Instability in Early Colorectal Lesions.

Bacher JW, Sievers CK, Albrecht DM, Grimes IC, Weiss JM, Matkowskyj KA, Agni RM, Vyazunova I, Clipson L, Storts DR, Thliveris AT, Halberg RB - PLoS ONE (2015)

Bottom Line: 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.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 difference in sensitivity between the LMR panel and the other panels was statistically significant (p<0.001).

View Article: PubMed Central - PubMed

Affiliation: Genetic Analysis Group, Promega Corporation, Madison, Wisconsin, United States of America; Department of Medicine, Division of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

The relative MSI sensitivity of the LMR markers was significantly higher than that of currently used markers.A total of 15 tumors were classified as MSI-High using the LMR panel, the MSI Analysis System or the NCI panel. The percentage of tumors that were scored as MSI-positive is shown for each individual marker. The relative sensitivity of the LMR panel was significantly higher than that of the MSI Analysis System (p = 0.0012) and the NCI panel (p<0.0038) using the t-test.
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pone.0132727.g003: The relative MSI sensitivity of the LMR markers was significantly higher than that of currently used markers.A total of 15 tumors were classified as MSI-High using the LMR panel, the MSI Analysis System or the NCI panel. The percentage of tumors that were scored as MSI-positive is shown for each individual marker. The relative sensitivity of the LMR panel was significantly higher than that of the MSI Analysis System (p = 0.0012) and the NCI panel (p<0.0038) using the t-test.

Mentions: Overall, 15 tumors were scored as MSI-High using the LMR panel compared to 9 for the NCI panel and 8 for the MSI Analysis System (Fig 2). This represents a 1.7 to 1.9-fold increase in detection of MSI-High lesions over currently used markers. The relative MSI sensitivity of individual LMR markers varied, but even the worst marker was more sensitive than the markers in the NCI panel and the MSI Analysis System (Fig 3). The sensitivity and specificity for detection of MMR-deficient lesions was estimated for a subset of 90 samples for which there was MMR expression data by IHC (Table 1). The overall sensitivity and specificity of the LMR panel for detection of MMR-deficient lesions was 100% and 96%, respectively. In comparison, the sensitivity and specificity of the MSI Analysis System was 67% and 100%; and for the NCI panel, 75% and 97%. The difference in sensitivity between the LMR panel and the both the MSI Analysis System and the NCI panel was statistically significant (z-test; p<0.001). The specificity of the LMR panel was not significantly different from the MSI Analysis System or the NCI panel (z-test; p = 0.252 and 0.899, respectively). Limitations for these estimates are that IHC testing was not performed on all samples and that in most cases the germline MMR mutation status was unknown. Therefore, the values may be overestimates and only refer to detection of mismatch-deficient lesions, not to detection of Lynch syndrome.


Improved Detection of Microsatellite Instability in Early Colorectal Lesions.

Bacher JW, Sievers CK, Albrecht DM, Grimes IC, Weiss JM, Matkowskyj KA, Agni RM, Vyazunova I, Clipson L, Storts DR, Thliveris AT, Halberg RB - PLoS ONE (2015)

The relative MSI sensitivity of the LMR markers was significantly higher than that of currently used markers.A total of 15 tumors were classified as MSI-High using the LMR panel, the MSI Analysis System or the NCI panel. The percentage of tumors that were scored as MSI-positive is shown for each individual marker. The relative sensitivity of the LMR panel was significantly higher than that of the MSI Analysis System (p = 0.0012) and the NCI panel (p<0.0038) using the t-test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4529134&req=5

pone.0132727.g003: The relative MSI sensitivity of the LMR markers was significantly higher than that of currently used markers.A total of 15 tumors were classified as MSI-High using the LMR panel, the MSI Analysis System or the NCI panel. The percentage of tumors that were scored as MSI-positive is shown for each individual marker. The relative sensitivity of the LMR panel was significantly higher than that of the MSI Analysis System (p = 0.0012) and the NCI panel (p<0.0038) using the t-test.
Mentions: Overall, 15 tumors were scored as MSI-High using the LMR panel compared to 9 for the NCI panel and 8 for the MSI Analysis System (Fig 2). This represents a 1.7 to 1.9-fold increase in detection of MSI-High lesions over currently used markers. The relative MSI sensitivity of individual LMR markers varied, but even the worst marker was more sensitive than the markers in the NCI panel and the MSI Analysis System (Fig 3). The sensitivity and specificity for detection of MMR-deficient lesions was estimated for a subset of 90 samples for which there was MMR expression data by IHC (Table 1). The overall sensitivity and specificity of the LMR panel for detection of MMR-deficient lesions was 100% and 96%, respectively. In comparison, the sensitivity and specificity of the MSI Analysis System was 67% and 100%; and for the NCI panel, 75% and 97%. The difference in sensitivity between the LMR panel and the both the MSI Analysis System and the NCI panel was statistically significant (z-test; p<0.001). The specificity of the LMR panel was not significantly different from the MSI Analysis System or the NCI panel (z-test; p = 0.252 and 0.899, respectively). Limitations for these estimates are that IHC testing was not performed on all samples and that in most cases the germline MMR mutation status was unknown. Therefore, the values may be overestimates and only refer to detection of mismatch-deficient lesions, not to detection of Lynch syndrome.

Bottom Line: 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.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 difference in sensitivity between the LMR panel and the other panels was statistically significant (p<0.001).

View Article: PubMed Central - PubMed

Affiliation: Genetic Analysis Group, Promega Corporation, Madison, Wisconsin, United States of America; Department of Medicine, Division of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus