Accuracy of four mononucleotide-repeat markers for the identification of DNA mismatch-repair deficiency in solid tumors
Year: 2018
Type: article
Abstract: BACKGROUND: To screen tumors with microsatellite instability (MSI) arising due to DNA mismatch repair deficiency (dMMR), a panel of five quasi-monomorphic mononucleotide-repeat markers amplified in a multiplex PCR (Pentaplex) are commonly used. In spite of its several strengths, the pentaplex assay is not robust at detecting the loss of MSH6-deficiency (dMSH6). In order to overcome this challenge, we designed this study to develop and optimize a panel of four quasi-monomorphic mononucleotide-repeat markers (Tetraplex) for identifying solid tumors with dMMR, especially dMSH6. METHODS: To improve the sensitivity for tumors with dMMR, we established a quasi-monomorphic variant range (QMVR) of 3-4 bp for the four Tetraplex markers. Thereafter, to confirm the accuracy of this assay, we examined 317 colorectal cancer (CRC) specimens, comprising of 105 dMMR [45 MutL homolog (MLH)1-deficient, 45 MutS protein homolog (MSH)2-deficient, and 15 MSH6-deficient tumors] and 212 MMR-proficient (pMMR) tumors as a test set. In addition, we analyzed a cohort of 138 endometrial cancers (EC) by immunohistochemistry to determine MMR protein expression and validation of our new MSI assay. RESULTS: Using the criteria of ≥ 1 unstable markers as MSI-positive tumor, our assay resulted in a sensitivity of 97.1% [95% confidence interval (CI) = 91.9-99.0%] for dMMR, and a specificity of 95.3% (95% CI = 91.5-97.4%) for pMMR CRC specimens. Among the 138 EC specimens, 41 were dMMR according to immunohistochemistry. Herein, our Tetraplex assay detected dMMR tumors with a sensitivity of 92.7% (95% CI = 80.6-97.5%) and a specificity of 97.9% (95% CI = 92.8-99.4%) for pMMR tumors. With respect to tumors with dMSH6, in the CRC-validation set, Tetraplex detected dMSH6 tumors with a sensitivity of 86.7% (13 of 15 dMSH6 CRCs), which was subsequently validated in the EC test set as well (sensitivity, 75.0%; 6 of 8 dMSH6 ECs). CONCLUSIONS: Our newly optimized Tetraplex system will help offer a robust and highly sensitive assay for the identification of dMMR in solid tumors.
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,890
Awards: G251590960, Novel treatment strategy for colorectal cancer based on genetic/ epigenetic information, Micro RNAs as promising therapeutic targets for anti-metastatic therapy in colorectal cancer, G2590648101, G312429407, G3173870227, Development of microRNA Biomarkers For Noninvasive Detection of Colorectal Cancer, G3411000325, Development of Non-invasive Screening Tool to Detect Colorectal Neoplasia., G3695502894, G4144402113, G4300560175, G6681643532, G6777199670, Innovation and clinical application of lung cancer screening modality using microbead-based technology, G7560054117, Preemptive Medicine to Solid Tumors based on Epigenomics, Construction of innovative preemptive medicine for gastrointestinal cancer especially including pancreatic cancer, Next Generation Sequencing-Based Approaches for the Development of Epigenetic Biomarkers for Predicting Therapeutic Outcome in Patients With Colorectal Cancer, Aspirin and Cancer Prevention in Lynch Syndrome: From Cell to Population Data, Methylation Biomarker Development for Noninvasive Detection of Colorectal Cancer, G9000004785, G9000016337, G9000182627, G9000208368, G9000226584, G9000270183, G913606961
OpenAlex ID: W2782769831