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Accurate Pan-Cancer Molecular Diagnosis of Microsatellite Instability by Single-Molecule Molecular Inversion Probe Capture and High-Throughput Sequencing.

ABSTRACT: BACKGROUND:Microsatellite instability (MSI) is an emerging actionable phenotype in oncology that informs tumor response to immune checkpoint pathway immunotherapy. However, there remains a need for MSI diagnostics that are low cost, highly accurate, and generalizable across cancer types. We developed a method for targeted high-throughput sequencing of numerous microsatellite loci with pan-cancer informativity for MSI using single-molecule molecular inversion probes (smMIPs). METHODS:We designed a smMIP panel targeting 111 loci highly informative for MSI across cancers. We developed an analytical framework taking advantage of smMIP-mediated error correction to specifically and sensitively detect instability events without the need for typing matched normal material. RESULTS:Using synthetic DNA mixtures, smMIPs were sensitive to at least 1% MSI-positive cells and were highly consistent across replicates. The fraction of identified unstable microsatellites discriminated tumors exhibiting MSI from those lacking MSI with high accuracy across colorectal (100% diagnostic sensitivity and specificity), prostate (100% diagnostic sensitivity and specificity), and endometrial cancers (95.8% diagnostic sensitivity and 100% specificity). MSI-PCR, the current standard-of-care molecular diagnostic for MSI, proved equally robust for colorectal tumors but evidenced multiple false-negative results in prostate (81.8% diagnostic sensitivity and 100% specificity) and endometrial (75.0% diagnostic sensitivity and 100% specificity) tumors. CONCLUSIONS:smMIP capture provides an accurate, diagnostically sensitive, and economical means to diagnose MSI across cancer types without reliance on patient-matched normal material. The assay is readily scalable to large numbers of clinical samples, enables automated and quantitative analysis of microsatellite instability, and is readily standardized across clinical laboratories.

SUBMITTER: Waalkes A

PROVIDER: S-EPMC6190826 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Publications

Accurate Pan-Cancer Molecular Diagnosis of Microsatellite Instability by Single-Molecule Molecular Inversion Probe Capture and High-Throughput Sequencing.

Waalkes Adam A Smith Nahum N Penewit Kelsi K Hempelmann Jennifer J Konnick Eric Q EQ Hause Ronald J RJ Pritchard Colin C CC Salipante Stephen J SJ

Clinical chemistry 20180409 6

<h4>Background</h4>Microsatellite instability (MSI) is an emerging actionable phenotype in oncology that informs tumor response to immune checkpoint pathway immunotherapy. However, there remains a need for MSI diagnostics that are low cost, highly accurate, and generalizable across cancer types. We developed a method for targeted high-throughput sequencing of numerous microsatellite loci with pan-cancer informativity for MSI using single-molecule molecular inversion probes (smMIPs).<h4>Methods</ ...[more]

PMID: 29632127

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Project description:PurposeMicrosatellite instability (MSI) and/or mismatch repair deficiency (MMR-D) testing has traditionally been performed in patients with colorectal (CRC) and endometrial cancer (EC) to screen for Lynch syndrome (LS)-associated cancer predisposition. The recent success of immunotherapy in high-frequency MSI (MSI-H) and/or MMR-D tumors now supports testing for MSI in all advanced solid tumors. The extent to which LS accounts for MSI-H across heterogeneous tumor types is unknown. Here, we establish the prevalence of LS across solid tumors according to MSI status.MethodsMSI status was determined using targeted next-generation sequencing, with tumors classified as MSI-H, MSI-indeterminate, or microsatellite-stable. Matched germline DNA was analyzed for mutations in LS-associated mismatch repair genes ( MLH1, MSH2, MSH6, PMS2, EPCAM). In patients with LS with MSI-H/I tumors, immunohistochemical staining for MMR-D was assessed.ResultsAmong 15,045 unique patients (more than 50 cancer types), LS was identified in 16.3% (53 of 326), 1.9% (13 of 699), and 0.3% (37 of 14,020) of patients with MSI-H, MSI-indeterminate, and microsatellite-stable tumors, respectively ( P < .001). Among patients with LS with MSI-H/I tumors, 50% (33 of 66) had tumors other than CRC/EC, including urothelial, prostate, pancreas, adrenocortical, small bowel, sarcoma, mesothelioma, melanoma, gastric, and germ cell tumors. In these patients with non-CRC/EC tumors, 45% (15 of 33) did not meet LS genetic testing criteria on the basis of personal/family history. Immunohistochemical staining of LS-positive MSI-H/I tumors demonstrated MMR-D in 98.2% (56 of 57) of available cases.ConclusionMSI-H/MMR-D is predictive of LS across a much broader tumor spectrum than currently appreciated. Given implications for cancer surveillance and prevention measures in affected families, these data support germline genetic assessment for LS for patients with an MSI-H/MMR-D tumor, regardless of cancer type or family cancer history.

Dataset Information

Accurate Pan-Cancer Molecular Diagnosis of Microsatellite Instability by Single-Molecule Molecular Inversion Probe Capture and High-Throughput Sequencing.

Publications

Accurate Pan-Cancer Molecular Diagnosis of Microsatellite Instability by Single-Molecule Molecular Inversion Probe Capture and High-Throughput Sequencing.

Similar Datasets

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