CMMRD Diagnosis via Microsatellite Instability Scoring
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Solution Overview
Problem
Diagnosing Constitutional Mismatch Repair Deficiency (CMMRD) cancer and MSI leukemia/lymphoma is challenging due to the broad spectrum of tumors and the presence of variants with unknown functional significance, leading to non-informative results and a lack of clear clinical features.
Innovation Solution
A method involving DNA sequence analysis of primary blood cells using massive parallel sequencing to detect microsatellite instability, calculating an ms.score by comparing read counts from patient samples to control samples, and using a limit regression model to differentiate between CMMRD and stable microsatellite cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If traditional diagnostic methods are used for CMMRD, then the diagnosis process becomes complex and time-consuming, but the diagnostic accuracy remains insufficient due to broad tumor spectrum and VUS variants
Solution Approach 1:
The invention extracts and focuses on a specific biomarker (microsatellite instability in blood cells) from the complex CMMRD diagnostic landscape. By isolating this particular genetic feature and developing a dedicated assay for it, the method simplifies the diagnostic process while maintaining high accuracy, avoiding the need to evaluate the entire broad spectrum of tumor characteristics
Solution Approach 2:
The invention changes the diagnostic parameter from evaluating tumor characteristics and germline mutations to measuring microsatellite instability in circulating blood cells. This parameter shift enables early detection before tumor development and provides a quantifiable metric (ms.score) that simplifies interpretation while improving diagnostic accuracy
2Loss of information
If germline mutation analysis is performed to diagnose CMMRD, then diagnostic information can be obtained, but variants with unknown functional significance lead to non-informative results
Solution Approach 1:
The invention introduces microsatellite instability measurement as an intermediary marker that reflects the functional consequence of MMR gene defects without requiring direct interpretation of germline variants. This intermediary approach bypasses the problem of VUS classification while still providing reliable diagnostic information about MMR deficiency status
Solution Approach 2:
The invention replaces the complex biological interpretation mechanism (assessing variant functional significance) with a straightforward molecular measurement mechanism (quantifying microsatellite instability). This substitution eliminates the need for subjective variant classification while providing objective, quantifiable diagnostic data
3Loss of time
If early detection of CMMRD is pursued to enable appropriate treatment, then patient outcomes can be improved, but the broad spectrum of tumors and lack of clear clinical features make detection difficult
Solution Approach 1:
The invention performs preliminary detection of microsatellite instability in blood cells before clinical symptoms or tumor development occur. By screening for this molecular marker in advance, the method enables early identification of CMMRD individuals, allowing intervention before the complex tumor spectrum manifests
Solution Approach 2:
The invention utilizes circulating blood cells that naturally carry the molecular signature of MMR deficiency to perform self-detection. The blood cells themselves provide the diagnostic information through their microsatellite instability profile, eliminating the need for complex clinical evaluation or tumor biopsy
Data Source
AI summary
The present invention relates to the diagnostic of CMMRD. In the present work, the inventors aimed to develop a test that could drastically simplify and improve the diagnosis of CMMRD based on DNA sequence analysis of primary blood cells (PBCs) from patients. Using massive parallel sequencing, they explored the possibility that MSI, the main genomic and functional consequence of constitutive MMR-deficiency, was likely to occur in CMMRD PBCs well before any transformation. Thus the present invention relates to a method of diagnosing a CMMRD cancer or a MSI leukemia/lymphoma in a patient in need thereof.