Reliable Pan-Cancer Microsatellite Instability Assessment by Using Targeted Next-Generation Sequencing Data

Area of Science:

• Oncology
• Genomics
• Cancer Diagnostics

Background:

• Microsatellite instability (MSI) and mismatch repair (MMR) deficiency are critical biomarkers for predicting response to immune checkpoint inhibitors in cancer patients.
• Accurate determination of MSI status is essential for guiding treatment decisions in various solid tumors.

Purpose of the Study:

• To evaluate the reliability of inferring MSI status from large-panel clinical targeted next-generation sequencing (NGS) data across diverse solid cancer types.
• To assess the performance of the MSIsensor program for MSI status determination using NGS data.

Main Methods:

• Analyzed MSI statuses of 12,288 advanced solid cancers using the MSIsensor program on Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets clinical NGS assay data.
• Determined cutoff scores, sensitivity, and specificity based on MSI polymerase chain reaction (PCR) and MMR immunohistochemistry for validation.

Main Results:

• MSIsensor identified MSI-high (MSI-H) status in 8% of colorectal cancers (CRCs) and 16% of uterine endometrioid cancers (UECs) using a score ≥ 10.
• Achieved 99.4% concordance with MSI PCR and/or MMR immunohistochemistry in validation cohorts of CRCs and UECs.
• Identified 68 MSI-H/MMR-deficient (MMR-D) tumors in non-CRC/UEC types, representing 35% of all identified MSI-H tumors.

Conclusions:

• MSI status can be reliably inferred from large-panel targeted NGS data using MSIsensor.
• Concurrent MSI testing by NGS is resource-efficient and potentially more sensitive for detecting MMR-D than traditional MSI PCR.
• NGS-based MSI testing facilitates the identification of MSI-H status across a broader range of cancer types beyond those typically screened.