Dataset Information

Performance evaluation for rapid detection of pan-cancer microsatellite instability with MANTIS.

ABSTRACT: In current clinical practice, microsatellite instability (MSI) and mismatch repair deficiency detection is performed with MSI-PCR and immunohistochemistry. Recent research has produced several computational tools for MSI detection with next-generation sequencing (NGS) data; however a comprehensive analysis of computational methods has not yet been performed. In this study, we introduce a new MSI detection tool, MANTIS, and demonstrate its favorable performance compared to the previously published tools mSINGS and MSISensor. We evaluated 458 normal-tumor sample pairs across six cancer subtypes, testing classification performance on variable numbers of target loci ranging from 10 to 2539. All three computational methods were found to be accurate, with MANTIS exhibiting the highest accuracy with 98.91% of samples from all six diseases classified correctly. MANTIS displayed superior performance among the three tools, having the highest overall sensitivity (MANTIS 97.18%, MSISensor 96.48%, mSINGS 76.06%) and specificity (MANTIS 99.68%, mSINGS 99.68%, MSISensor 98.73%) across six cancer types, even with loci panels of varying size. Additionally, MANTIS also had the lowest resource consumption (<1% of the space and <7% of the memory required by mSINGS) and fastest running times (49.6% and 8.7% of the running times of MSISensor and mSINGS, respectively). This study highlights the potential utility of MANTIS in classifying samples by MSI-status, allowing its incorporation into existing NGS pipelines.

SUBMITTER: Kautto EA

PROVIDER: S-EPMC5352334 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Performance evaluation for rapid detection of pan-cancer microsatellite instability with MANTIS.

Kautto Esko A EA Bonneville Russell R Miya Jharna J Yu Lianbo L Krook Melanie A MA Reeser Julie W JW Roychowdhury Sameek S

Oncotarget 20170101 5

In current clinical practice, microsatellite instability (MSI) and mismatch repair deficiency detection is performed with MSI-PCR and immunohistochemistry. Recent research has produced several computational tools for MSI detection with next-generation sequencing (NGS) data; however a comprehensive analysis of computational methods has not yet been performed. In this study, we introduce a new MSI detection tool, MANTIS, and demonstrate its favorable performance compared to the previously publishe ...[more]

PMID: 27980218

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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.

Project description:BackgroundMicrosatellite instability (MSI) is a key biomarker for cancer immunotherapy and prognosis. Integration of MSI testing into a next-generation-sequencing (NGS) panel could save tissue sample, reduce turn-around time and cost, and provide MSI status and comprehensive genomic profiling in single test. We aimed to develop an MSI calling model to detect MSI status along with the NGS panel-based profiling test using tumor-only samples.MethodsFrom January 2019 to December 2020, a total of 174 colorectal cancer (CRC) patients were enrolled, including 31 MSI-high (MSI-H) and 143 microsatellite stability (MSS) cases. Among them, 56 paired tumor and normal samples (10 MSI-H and 46 MSS) were used for modeling, and another 118 tumor-only samples were used for validation. MSI polymerase chain reaction (MSI-PCR) was performed as the gold standard. A baseline was built for the selected microsatellite loci using the NGS data of 56 normal blood samples. An MSI detection model was constructed by analyzing the NGS data of tissue samples. The performance of the model was compared with the results of MSI-PCR.ResultsWe first intersected the target genomic regions of the NGS panels used in this study to select common microsatellite loci. A total of 42 loci including 23 mononucleotide repeat sites and 19 longer repeat sites were candidates for modeling. As mononucleotide repeat sites are more sensitive and specific for detecting MSI status than sites with longer length motif and the mononucleotide repeat sites performed even better than the total sites, a model containing 23 mononucleotide repeat sites was constructed and named Colorectal Cancer Microsatellite Instability test (CRC-MSI). The model achieved 100% sensitivity and 100% specificity when compared with MSI-PCR in both training and validation sets. Furthermore, the CRC-MSI model was robust with the tumor content as low as 6%. In addition, 8 out of 10 MSI-H samples showed alternations in the four mismatch repair genes ( MLH1 , MSH2 , MSH6 , and PMS2 ).ConclusionMSI status can be accurately determined along the targeted NGS panels using only tumor samples. The performance of mononucleotide repeat sites surpasses loci with longer repeat motif in MSI calling.

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Performance evaluation for rapid detection of pan-cancer microsatellite instability with MANTIS.

Publications

Performance evaluation for rapid detection of pan-cancer microsatellite instability with MANTIS.

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