Dataset Information

Detection of Mismatch Repair Deficiency and Microsatellite Instability in Colorectal Adenocarcinoma by Targeted Next-Generation Sequencing.

ABSTRACT: 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.

SUBMITTER: Nowak JA

PROVIDER: S-EPMC5225299 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Publications

Detection of Mismatch Repair Deficiency and Microsatellite Instability in Colorectal Adenocarcinoma by Targeted Next-Generation Sequencing.

Nowak Jonathan A JA Yurgelun Matthew B MB Bruce Jacqueline L JL Rojas-Rudilla Vanesa V Hall Dimity L DL Shivdasani Priyanka P Garcia Elizabeth P EP Agoston Agoston T AT Srivastava Amitabh A Ogino Shuji S Kuo Frank C FC Lindeman Neal I NI Dong Fei F

The Journal of molecular diagnostics : JMD 20161115 1

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% s ...[more]

PMID: 27863258

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Project description:ImportancePrimary resistance to immune checkpoint inhibitors is observed in 10% to 40% of patients with metastatic colorectal cancer (mCRC) displaying microsatellite instability (MSI) or defective mismatch repair (dMMR).ObjectiveTo investigate possible mechanisms underlying primary resistance to immune checkpoint inhibitors of mCRC displaying MSI or dMMR.Design, setting, and participantsThis post hoc analysis of a single-center, prospective cohort included 38 patients with mCRC diagnosed as MSI or dMMR by local laboratories and entered into trials of immune checkpoint inhibitors between January 1, 2015, and December 31, 2016. The accuracy of MSI or dMMR status was also assessed in a retrospective cohort comprising 93 cases of mCRC that were diagnosed as MSI or dMMR between January 1, 1998, and December 31, 2016, in 6 French hospitals. Primary resistance of mCRC was defined as progressive disease according to Response Evaluation Criteria in Solid Tumors criteria, 6 to 8 weeks after initiation of immune checkpoint inhibitors, without pseudo-progression. All tumor samples were reassessed for dMMR status using immunohistochemistry with antibodies directed against MLH1, MSH2, MSH6, and PMS2, and for MSI using polymerase chain reaction with pentaplex markers and with the HSP110 T17 (HT17) repeat.Main outcomes and measuresThe primary outcome was positive predictive value.ResultsAmong the 38 patients (15 women and 23 men; mean [SD] age, 55.6 [13.7] years) in the study with mCRC displaying MSI or dMMR, primary resistance to immune checkpoint inhibitors was observed in 5 individuals (13%). Reassessment of the status of MSI or dMMR revealed that 3 (60%) of these 5 resistant tumors were microsatellite stable or displayed proficient mismatch repair. The positive predictive value of MSI or dMMR status assessed by local laboratories was therefore 92.1% (95% CI, 78.5%-98.0%). In the retrospective cohort of 93 patients (44 women and 49 men; mean [SD] age, 56.8 [18.3] years) without immune checkpoint inhibitor treatment, misdiagnosis of the MSI or dMMR status by local assessment was 10% (n = 9), with a positive predictive value of 90.3% (95% CI, 82.4%-95.0%). Testing for MSI with the HT17 assay confirmed the MSI or dMMR status in 2 of 4 cases showing discrepant results between immunohistochemistry and pentaplex polymerase chain reaction (ie, dMMR but microsatellite stable).Conclusions and relevancePrimary resistance of mCRC displaying MSI or dMMR to immune checkpoint inhibitors is due mainly to misdiagnosis of their MSI or dMMR status. Larger studies are required to confirm these findings. Microsatellite instability or dMMR status should be tested routinely using both immunohistochemistry and polymerase chain reaction methods prior to treatment with immune checkpoint inhibitors.

Dataset Information

Detection of Mismatch Repair Deficiency and Microsatellite Instability in Colorectal Adenocarcinoma by Targeted Next-Generation Sequencing.

Publications

Detection of Mismatch Repair Deficiency and Microsatellite Instability in Colorectal Adenocarcinoma by Targeted Next-Generation Sequencing.

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