Clustered Mutation Signatures Reveal that Error-Prone DNA Repair Targets Mutations to Active Genes

Area of Science:

• Genomics
• Cancer Biology
• Molecular Biology

Background:

• Identifying the specific causes of genomic mutations is challenging due to multiple processes yielding similar nucleotide changes.
• Clustered mutations serve as more accurate indicators of mutagenic processes than individual mutations.
• Understanding these signatures is crucial for cancer research and treatment.

Purpose of the Study:

• To identify and characterize distinct clustered mutation signatures across a large dataset of tumor genomes.
• To associate these signatures with specific mutagenic factors such as chemical exposure and DNA repair pathways.
• To investigate the genomic targeting of these mutations in different cancer types.

Main Methods:

• Analysis of over 1,000 tumor genomes to identify clustered mutation patterns.
• Development and application of computational methods to detect mutation signatures.
• Correlation of identified signatures with known mutagens (e.g., tobacco, UV, alcohol) and DNA repair mechanisms (e.g., MMR, POLH).

Main Results:

• Nine distinct clustered mutation signatures were identified.
• Three signatures were linked to APOBEC mutational activity.
• Three signatures were associated with tobacco smoking, and one with translesion DNA polymerase eta (POLH).
• In lymphoid cells, mutations targeted promoters, consistent with somatic hypermutation.
• In solid tumors, mutations targeted H3K36me3 chromatin in an MMR-dependent manner, linked to UV and alcohol exposure.

Conclusions:

• Clustered mutation signatures provide a powerful tool for dissecting mutagenic processes in cancer.
• Specific signatures are associated with distinct environmental exposures and endogenous factors.
• The targeting of active gene chromatin by mutations, particularly in an MMR-deficient context, highlights a significant mechanism contributing to cancer development and driver mutations.