Bibliographic Reference
Nik-Zainal, S., Alexandrov, L. B., Wedge, D. C., Van Loo, P., Greenman, C. D., Raine, K., … & Stratton, M. R. (2012). Mutational processes molding the genomes of 21 breast cancers. Cell, 149(5), 979–993. https://doi.org/10.1016/j.cell.2012.04.024
Core Argument
The patterns of somatic mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. By generating comprehensive catalogs of somatic mutations from 21 breast cancers and applying mathematical methods (non-negative matrix factorization), distinct mutational signatures of the underlying processes can be extracted from the passenger mutation burden — bypassing the confounding effects of selection on driver mutations.
Methods
Whole-genome sequencing of 21 breast cancers (all primary, treatment-naive) and matched normal DNA. Comprehensive catalog of all somatic mutations: substitutions, indels, rearrangements. Non-negative matrix factorization (NMF) to decompose the mutational spectra into distinct signatures. Phylogenetic reconstruction using subclonal VAF distributions. Integration with clinical features (BRCA1/2 status, ER status).
Key Findings
- Multiple distinct single-nucleotide substitution signatures were extracted, including signatures associated with age (signature 1A/B, C>T at NpCpG), BRCA1/2 deficiency (signature 3, characterized by specific substitution patterns), and APOBEC enzyme activity (signature 2 and 13, C>T and C>G at TpC).
- A remarkable phenomenon of localized hypermutation, termed “kataegis” (Greek for “thunderstorm”), was discovered — regions of clustered C>T and C>G mutations at TpC dinucleotides that frequently colocalize with sites of somatic structural rearrangement.
- Cancers with BRCA1 or BRCA2 mutations exhibit a characteristic combination of substitution mutation signatures and a distinctive profile of small deletions (longer indels, microhomology-mediated).
- Complex relationships exist between somatic mutation prevalence and transcription — regions of higher gene expression show lower mutation rates, consistent with transcription-coupled repair.
- Most rearrangements in breast cancers are of two types: tandem duplications and deletions. BRCA1-mutant cancers show a distinct rearrangement signature enriched for small tandem duplications.
- Subclonal mutational architecture was reconstructed, revealing the relative timing of mutational processes — some signatures (like APOBEC) appear to act later in tumor evolution.
Concepts Introduced or Used
mutational-signature, kataegis, passenger-mutation, driver-mutation, subclonal-architecture, APOBEC-mutagenesis, BRCA-deficiency-signature, transcription-coupled-repair, tandem-duplication, chromothripsis, clonal-evolution, non-negative-matrix-factorization, substitution-spectrum, indel-signature, rearrangement-signature
Entities Referenced
- BRCA1, BRCA2, TP53, APOBEC3A, APOBEC3B, PIK3CA, GATA3
- Wellcome Trust Sanger Institute, International Cancer Genome Consortium (ICGC)
- Non-negative matrix factorization (NMF)
- Whole-genome sequencing
Limitations
- Only 21 cases (discovery cohort) — mutational processes that are rare or of low magnitude may be missed.
- The study is primarily descriptive — the mechanistic basis of most mutational signatures remains unknown.
- APOBEC involvement is inferred from mutational pattern similarity, not directly demonstrated.
- Each cancer was sampled at a single time point; longitudinal dynamics of mutational processes could not be assessed.
Relevance to Clonal Evolution
This is a foundational paper for the field of mutational signature analysis. It established the methodology for extracting biologically meaningful mutational processes from whole-genome catalogs of passenger mutations, and introduced the concept of kataegis. These signatures provide a “fossil record” of the mutational exposures and repair deficiencies that have shaped a cancer’s evolutionary history. The subclonal timing analysis demonstrated that different mutational processes can be active at different phases of clonal evolution.