Genomic Microsatellite Signatures Identify Germline Mismatch Repair Deficiency and Risk of Cancer Onset.

Area of Science:

• Genomics
• Oncology
• Cancer Diagnostics

Background:

• Accurate diagnosis of Mismatch Repair Deficiency (MMRD) is critical for managing cancer predisposition syndromes like constitutional mismatch repair deficiency (CMMRD).
• Existing diagnostic methods for MMRD are often complex and inconsistent, particularly in pediatric cancers and for identifying germline MMRD.

Purpose of the Study:

• To develop and validate a functional Low-pass Genomic Instability Characterization (LOGIC) assay for detecting MMRD.
• To compare the diagnostic performance of LOGIC against established assays and assess its utility in various tissue types and patient cohorts.

Main Methods:

• Development and analysis of the LOGIC assay.
• Comparative analysis of LOGIC against tumor mutational burden, immunohistochemistry, and microsatellite instability panel.
• Application of LOGIC to normal tissues from CMMRD patients with comprehensive clinical data.

Main Results:

• LOGIC demonstrated 100% sensitivity and specificity for MMRD in childhood cancers (N=376), significantly outperforming other methods.
• LOGIC successfully differentiated CMMRD from other cancer predisposition syndromes using blood and saliva DNA (n=277).
• In normal tissues, MMRDness scores varied by tissue type and increased over time, correlating with earlier cancer onset in CMMRD patients.

Conclusions:

• The LOGIC assay is a reliable tool for diagnosing MMRD across multiple cancer types and in normal tissues.
• LOGIC can facilitate rapid germline MMRD diagnosis, inform therapeutic strategies, and guide personalized surveillance for CMMRD individuals.