Microsatellite Scoring for MMRD and PPD Cancer Classification
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Solution Overview
Problem
Current methods are inadequate for identifying patients with constitutional mismatch repair deficiency (CMMRD), mismatch repair deficiency (MMD) cancers, polymerase proofreading deficiency (PPD) cancers, and predicting responses to immunotherapy, particularly due to limited understanding of microsatellite instability and indel signatures in cancer.
Innovation Solution
Calculating MS-sig1 (MMRDness score) and MS-sig2 (POLEness score) from sequencing data to characterize biological samples, determining the prevalence of microsatellite insertions and deletions, and using these scores to select appropriate therapies, including immune checkpoint inhibitor treatments.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If traditional MSI detection methods using a limited panel of microsatellites are used, then the assay is simple and quick, but it leads to misclassification of MMRD cancers and limited scope in detecting polymerase mutant cancers
Solution Approach 1:
The patent segments the microsatellite analysis into two distinct scoring systems: MS-sig1 (MMRDness score) for detecting MMRD and MS-sig2 (POLEness score) for detecting polymerase mutations. This segmentation allows each score to be optimized for its specific detection target, resolving the contradiction by maintaining operational simplicity while improving classification precision through specialized detection mechanisms.
Solution Approach 2:
The patent transitions from traditional two-dimensional MSI-H/MSS classification to a three-dimensional scoring system incorporating MMRDness scores, POLEness scores, and their interaction. This dimensional expansion enables more precise characterization of cancer types, particularly identifying MMRD cancers that were previously misclassified, while maintaining the simplicity of the scoring calculation method.
2Loss of information
If polymerase mutations are considered, then a more complete understanding of DNA repair deficiency is achieved, but the impact on microsatellite instability accumulation remains largely unknown and difficult to detect
Solution Approach 1:
The patent introduces MS-sig2 (POLEness score) as an intermediary metric that quantifies the impact of polymerase mutations on microsatellite instability. This intermediary scoring system translates the complex biological effect of polymerase mutations into a measurable parameter, enabling detection and characterization of polymerase mutant cancers without requiring direct genetic sequencing of polymerase genes.
Solution Approach 2:
The patent replaces direct mechanical detection of polymerase mutations with an indirect measurement approach using microsatellite indel signatures. Instead of directly analyzing polymerase gene sequences, the system measures the functional consequence of polymerase mutations on microsatellite stability, substituting a simpler, more scalable measurement method for complex genetic analysis.
3Measurement precision
If comprehensive analysis of MMRD and PPD is performed, then accurate identification of replication repair deficiencies is achieved, but the complexity of analysis increases
Solution Approach 1:
The patent divides the complex analysis into two independent, modular scoring systems: MS-sig1 for MMRD detection and MS-sig2 for PPD detection. Each module can be calculated separately from sequencing data, maintaining high accuracy for identifying replication repair deficiencies while reducing overall system complexity through modular design. The independence of the two scoring systems allows for parallel processing and simplified implementation.
Data Source
AI summary
The disclosure features in some aspects methods for identifying subjects with constitutional mismatch repair deficiency (CMMRD), a mismatch repair deficiency (MMD) cancer, a polymerase proofreading deficiency (PPD) cancer, and/or a MMD&PPD cancer. The disclosure also features in some aspects methods for predicting response of a subject to immunotherapy.