Constitutional Mismatch Repair Deficiency in Genetic Oncology

Constitutional mismatch repair deficiency (CMMRD) is a rare, autosomal recessive cancer predisposition syndrome arising from biallelic germline mutations in one of the core DNA mismatch repair (MMR) genes—MLH1, MSH2, MSH6 or PMS2. From birth, affected individuals harbour a fully compromised DNA repair system, leading to an exceptionally high burden of somatic mutations and early‐onset malignancies. The tumour spectrum in CMMRD is broad and often includes high‐grade gliomas, haematological neoplasms and gastrointestinal cancers. Clinical presentation can be heterogeneous, with some patients exhibiting café‐au‐lait macules, developmental venous anomalies of the brain or pilomatricomas, while others display few overt cutaneous signs. Diagnostic challenges stem from pseudogene interference (notably in PMS2), variants of uncertain significance and overlap with Lynch syndrome phenotypes. Recent advances in low‐level microsatellite instability (MSI) assays, both in blood and tumour tissue, have improved sensitivity and specificity for CMMRD detection. Therapeutic strategies are evolving rapidly: hypermutated CMMRD tumours generate abundant neoantigens, rendering them susceptible to immune checkpoint inhibitors and potentially to personalized neoantigen vaccines. Surveillance protocols incorporating regular imaging and endoscopic screening aim to detect malignancies at a treatable stage. Family members of patients benefit from targeted genetic counselling and cascade testing, underscoring the global importance of early recognition and management of this under-reported syndrome.

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Constitutional Mismatch Repair Deficiency in Genetic Oncology publication trend

The graph below shows the total number of articles in constitutional mismatch repair deficiency in genetic oncology across all publications each year (not limited to Nature Index journals).

Technical terms

Constitutional mismatch repair deficiency (CMMRD): A hereditary cancer syndrome caused by inherited bi-allelic mutations in mismatch repair genes, leading to defective DNA repair, hypermutation and early-onset tumours.

Mismatch repair (MMR): A DNA repair pathway that corrects replication errors such as base–base mismatches and insertion–deletion loops to maintain genomic stability.

Microsatellite instability (MSI): Variability in the length of short tandem repeats in DNA arising from impaired MMR, used as a biomarker for repair deficiency.

Immune checkpoint inhibitor: A class of immunotherapy drugs that block regulatory pathways (e.g., PD-1/PD-L1) in T cells, enhancing anti-tumour immune responses.

Neoantigen: A novel peptide presented by tumour cells, generated from tumour-specific mutations, that can be recognised as foreign by the immune system.

References

1. Precision immuno-oncology approach for four malignant tumors in siblings with constitutional mismatch repair deficiency syndrome. npj Precision Oncology (2024).
2. A Validated Highly Sensitive Microsatellite Instability Assay Accurately Identifies Individuals Harboring Biallelic Germline PMS2 Pathogenic Variants in Constitutional Mismatch Repair Deficiency. Clinical Chemistry (2024).
3. A sensitive and scalable microsatellite instability assay to diagnose constitutional mismatch repair deficiency by sequencing of peripheral blood leukocytes. Human Mutation (2019).
4. Multiple Brain Developmental Venous Anomalies as a Marker for Constitutional Mismatch Repair Deficiency Syndrome. American Journal of Neuroradiology (2018).