Abstract
BackgroundA systematic review was conducted to assess the diagnostic test accuracy of polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing for identifying Lynch syndrome in patients with colorectal cancer (CRC). Unlike previous reviews, this was based on assessing MSI testing against best practice for the reference standard, and included CRC populations that were unselected, age-limited or high-risk for Lynch syndrome.MethodsSingle- and two-gate diagnostic test accuracy studies, or similar, were identified, assessed for inclusion, data extracted and quality appraised by two reviewers according to a pre-specified protocol. Sensitivity of MSI testing was estimated for all included studies. Specificity, likelihood ratios and predictive values were estimated for studies that were not based on high-risk samples. Narrative synthesis was conducted.ResultsNine study samples were included. When MSI-Low results were considered to be negative, sensitivity estimates ranged from 67% (95% CI 47, 83) to 100% (95% CI 94, 100). Three studies contributed to estimates of both sensitivity and specificity, with specificity ranging from 61% (95% CI 57, 65), to 93% (95% CI 89, 95). Good sensitivity was achieved at the expense of specificity. When MSI-L was considered to be positive (effectively lowering the threshold for a positive index test result) sensitivity increased and specificity decreased. Between-study heterogeneity in both the MSI and reference standard testing, combined with the low number of studies contributing to both sensitivity and specificity estimates, precluded pooling by meta-analysis.ConclusionsMSI testing is an effective screening test for Lynch syndrome. However, there is significant uncertainty surrounding what balance of sensitivity and specificity will be achieved in clinical practice and how this relates to specific characteristics of the test (such as the panel of markers used or the thresholds used to denote a positive test).
Highlights
A systematic review was conducted to assess the diagnostic test accuracy of polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing for identifying Lynch syndrome in patients with colorectal cancer (CRC)
Lynch syndrome is caused by heritable constitutional pathogenic mutations in the mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2) or, rarely, by certain mutations in nearby genes that affect expression of the adjacent MMR gene
The best method for diagnosing Lynch syndrome is comprehensive screening for constitutional mutations in the MMR genes and EPCAM, using a combination of (i) DNA sequencing
Summary
A systematic review was conducted to assess the diagnostic test accuracy of polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing for identifying Lynch syndrome in patients with colorectal cancer (CRC). Due to the fact that there is a high probability of loss of MMR function in Lynch syndrome cancers, and that tumours which have lost MMR function display microsatellite instability, one such test is microsatellite instability (MSI) testing This involves polymerase chain reaction (PCR) amplification of DNA markers (using tumour tissue and healthy tissue). When a trimodal categorisation is initially used, a decision must be taken as to whether MSI-Low (MSI-L) will be further categorised as a positive or negative test result
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