Two main mutational processes operate in the absence of DNA mismatch repair

Area of Science:

• Genomics
• Cancer Biology
• Molecular Oncology

Background:

• Inactivation of DNA mismatch repair (MMR) leads to high rates of base substitution mutations in tumors.
• Somatic mutations in MMR-deficient tumors are associated with enhanced responses to immunotherapy.
• Existing mutation signatures for MMR deficiency show discrepancies between tumor and cell line data.

Purpose of the Study:

• To resolve discrepancies in mutation signatures associated with MMR deficiency.
• To identify robust base substitution signatures characterizing MMR deficiency across different sequencing contexts (exome vs. whole genome).
• To investigate factors influencing the mutation spectrum in MMR-deficient cells.

Main Methods:

• Reanalysis of mutation data from MMR-deficient tumors and cell lines.
• Application of non-negative matrix factorization to derive base substitution signatures.
• Comparison of derived signatures with existing COSMIC signatures for MMR deficiency detection.
• Analysis of mutation spectrum variations based on sequencing context, MMR gene, tissue type, mutational burden, and cell type.

Main Results:

• Two novel base substitution signatures were derived, effectively describing mutagenesis in both tumor and cell line samples.
• These new signatures outperform existing COSMIC signatures in identifying MMR-deficient tumors.
• The relative contribution of the two signatures is influenced by exome versus whole-genome sequencing.
• No significant influence of inactivated MMR gene, tissue type, mutational burden, or patient age on the mutation spectrum was observed.
• Tumors showed a greater contribution from the CpG mutational process compared to cultured cells.

Conclusions:

• Two distinct mutational processes operate in MMR-deficient genomes.
• The derived signatures provide a more accurate method for identifying MMR-deficient tumors.
• Understanding these mutational processes can refine cancer diagnostics and therapeutic strategies.