Mutational Signatures in Cancer Genomics

Mutational signatures are distinctive patterns of somatic mutations imprinted on the cancer genome by endogenous processes such as DNA replication errors and repair deficiencies, and by exogenous factors including ultraviolet light, tobacco smoke and environmental carcinogens. By deconvoluting the catalogue of base substitutions, insertions and deletions in tumour sequences, researchers can infer the underlying mutational processes, trace their temporal dynamics and link them to specific aetiologies. Computational frameworks now enable the extraction of signatures from individual tumours and large cohorts, revealing contributions from defective homologous recombination, APOBEC cytidine deaminase activity, reactive oxygen species and other modulators of genome stability. The characterisation of these signatures has practical implications for biomarker discovery, risk stratification and the design of precision therapies, since certain signatures predict sensitivity to DNA‐damage response inhibitors or chemotherapeutic regimens. Global surveys of mutational footprints across cancer types have provided a systematic atlas of processes operative in tumour evolution, improving our understanding of cancer aetiology, informing prevention strategies and guiding translational applications in diagnosis and treatment.

Research from Nature Portfolio

Advances in analytical methods have refined the discovery and attribution of mutational signatures. A novel computational pipeline demonstrates superior performance in both signature extraction and quantification across thousands of cancer genomes, uncovering nine previously unrecognised small‐indel signatures and resolving ambiguities in uninformative “flat” patterns. This enhanced catalogue paves the way for standardised best practices in mutational signature analysis. In paediatric oncology, a comprehensive study of nearly eight hundred whole‐genome‐sequenced tumours from twenty‐seven disease subtypes identified a limited repertoire of active signatures compared with adult cancers, highlighted distinct homologous recombination repair deficiency patterns and reported a novel indel signature affecting noncoding and coding regions. These findings establish a paediatric‐specific framework for biomarker development. In oesophageal adenocarcinoma, longitudinal sampling across premalignant and metastatic stages revealed that C[T> C/G]T‐enriched signatures dominate early tumourigenesis and associate with TP53 mutations and genomic instability, while APOBEC‐related activity persists into advanced disease. Concurrent alterations in base and nucleotide excision repair pathways were linked to clinical prognosis, underscoring the dynamic interplay between mutational processes and tumour evolution.

Mutational Signatures in Cancer Genomics publication trend

The graph below shows the total number of articles in mutational signatures in cancer genomics across all publications each year (not limited to Nature Index journals).

Technical terms

Mutational signature: A characteristic pattern of somatic mutations reflecting a specific mutational process.

Single‐base substitution (SBS): A somatic point mutation in which one nucleotide is replaced by another.

Indel signature: A pattern of small insertions and deletions attributable to particular DNA damage or repair defects.

APOBEC enzymes: A family of cytidine deaminases that can induce C > T and C > G mutations in DNA.

Homologous recombination repair defect: Loss of accurate DNA double‐strand break repair, often leading to characteristic deletion signatures and genomic instability.

References

1. Accurate and sensitive mutational signature analysis with MuSiCal. Nature Genetics (2024).
2. Comprehensive analysis of mutational signatures reveals distinct patterns and molecular processes across 27 pediatric cancers. Nature Cancer (2023).
3. Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma. Nature Communications (2023).
4. Mutation rate heterogeneity at the sub-gene scale due to local DNA hypomethylation. Nucleic Acids Research (2024).
5. Mutational processes of tobacco smoking and APOBEC activity generate protein-truncating mutations in cancer genomes. Science Advances (2023).
6. Sequence dependencies and mutation rates of localized mutational processes in cancer. Genome Medicine (2023).
7. The repertoire of mutational signatures in human cancer. Nature (2020).