Detection of Mismatch Repair Deficiency and Microsatellite Instability in Colorectal Adenocarcinoma by Targeted Next-Generation Sequencing
| Autor: | Elizabeth P. Garcia, Priyanka Shivdasani, Frank C. Kuo, Vanesa Rojas-Rudilla, Amitabh Srivastava, Neal I. Lindeman, Shuji Ogino, Agoston T. Agoston, Matthew B. Yurgelun, Dimity Hall, Jonathan A. Nowak, Fei Dong, Jacqueline L. Bruce |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities DNA Mutational Analysis Adenocarcinoma Biology medicine.disease_cause DNA Mismatch Repair DNA sequencing Pathology and Forensic Medicine 03 medical and health sciences 0302 clinical medicine medicine Humans Genetics Mutation Base Sequence High-Throughput Nucleotide Sequencing Microsatellite instability Regular Article Mismatch Repair Protein medicine.disease Colorectal Neoplasms Hereditary Nonpolyposis digestive system diseases 030104 developmental biology 030220 oncology & carcinogenesis Molecular Medicine Microsatellite Microsatellite Instability DNA mismatch repair Genes Neoplasm Microsatellite Repeats |
| Zdroj: | The Journal of Molecular Diagnostics. 19:84-91 |
| ISSN: | 1525-1578 |
| DOI: | 10.1016/j.jmoldx.2016.07.010 |
| Popis: | Mismatch repair protein deficiency (MMR-D) and high microsatellite instability (MSI-H) are features of Lynch syndrome–associated colorectal carcinomas and have implications in clinical management. We evaluate the ability of a targeted next-generation sequencing panel to detect MMR-D and MSI-H based on mutational phenotype. Using a criterion of >40 total mutations per megabase or >5 single-base insertion or deletion mutations in repeats per megabase, sequencing achieves 92% sensitivity and 100% specificity for MMR-D by immunohistochemistry in a training cohort of 149 colorectal carcinomas and 91% sensitivity and 98% specificity for MMR-D in a validation cohort of 94 additional colorectal carcinomas. False-negative samples are attributable to tumor heterogeneity, and next-generation sequencing results are concordant with analysis of microsatellite loci by PCR. In a subset of 95 carcinomas with microsatellite analysis, sequencing achieves 100% sensitivity and 99% specificity for MSI-H in the combined training and validation set. False-positive results for MMR-D and MSI-H are attributable to ultramutated cancers with POLE mutations, which are confirmed by direct sequencing of the POLE gene and are detected by mutational signature analysis. These findings provide a framework for a targeted tumor sequencing panel to accurately detect MMR-D and MSI-H in colorectal carcinomas. |
| Databáze: | OpenAIRE |
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