Constitutional Microsatellite Instability, Genotype, and Phenotype Correlations in Constitutional Mismatch Repair...

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Constitutional mismatch repair deficiency (CMMRD) is a rare, inherited childhood cancer syndrome.
• Constitutional microsatellite instability (cMSI) is a hallmark of CMMRD and may indicate cancer risk.

Purpose of the Study:

• To quantify cMSI in a large CMMRD cohort.
• To explore genotype-phenotype correlations using novel blood-based MSI markers.

Main Methods:

• Genome and amplicon sequencing of CMMRD, Lynch syndrome, and control blood samples.
• Development and validation of a cMSI scoring method using 32 mononucleotide repeats.
• Comparison of the novel assay's performance against established methods.

Main Results:

• The novel cMSI assay demonstrated 100% sensitivity and specificity in detecting CMMRD.
• cMSI scores correlated with specific mismatch repair gene variants (e.g., MSH6 deficiency, missense vs. truncating variants).
• cMSI score did not correlate with age at first tumor diagnosis.

Conclusions:

• An inexpensive, scalable cMSI assay improves CMMRD detection.
• cMSI is linked to mismatch repair genotype but not clinical phenotype, limiting its use as a cancer risk predictor.