A new genomic study has revealed diverse and treatment-influenced mutational patterns in tumours associated with Constitutional Mismatch Repair Deficiency (CMMRD), a rare genetic disorder that predisposes children to multiple early-onset cancers. CMMRD is caused by bi-allelic germline mutations in mismatch repair (MMR) genes, which normally help maintain DNA stability.
Researchers analysed 41 tumours from 17 individuals with CMMRD to investigate the mutational processes driving tumor development. The study found that the patterns of mutations varied significantly depending on the specific MMR gene affected, tumor type, and treatment history.
In addition to commonly observed mutations, the analysis detected somatic polymerase proofreading mutations typically found in brain tumours. Interestingly, similar mutations were identified in a case of T-cell lymphoblastic lymphoma, indicating that these mutational processes are not limited to brain cancers.
Two secondary hematological malignancies that developed after treatment with temozolomide showed distinct mutational signatures, suggesting a strong influence of prior chemotherapy on tumor evolution. Moreover, a notable indel mutation signature, characterised by one-base pair cytosine insertions in cytosine homopolymer regions, was observed in 54% of the tumours examined.
The findings underscore the complexity of tumor development in CMMRD and the role of both genetic and environmental factors in shaping mutation patterns. This comprehensive analysis enhances the understanding of CMMRD tumor biology and may inform more targeted treatment strategies for affected individuals.
Reference
Weijers DD et al. Unraveling mutagenic processes influencing the tumor mutational patterns of individuals with constitutional mismatch repair deficiency. Nat Commun. 2025; doi.org/10.1038/s41467-025-59775-2.
