APOBEC Mutagenesis: An Internal Source of Cancer Mutations

From Antiviral Defence to Genome Damage

APOBEC3A and APOBEC3B act on single-stranded DNA, which is exposed transiently during replication, transcription and repair. Deamination of cytosine produces uracil; subsequent processing yields C>T transitions or, via an abasic intermediate, C>G transversions.

The mutations often occur in clusters along one strand, a pattern called kataegis, reflecting a processive burst of deamination on a stretch of exposed single-stranded DNA.

Timing and Subclonality

APOBEC activity tends to be episodic rather than constant. As a result the signature is frequently enriched among subclonal mutations, meaning it was active after the most recent common ancestor of the tumour and continues to generate heterogeneity.

This makes APOBEC a driver of ongoing genomic diversification, which has implications for how representative any single biopsy is.

Link to Treatment Resistance

Laboratory work has shown that some targeted therapies can induce APOBEC3A in drug-tolerant persister cells, accelerating mutation accrual and the emergence of resistance. APOBEC signatures are also enriched in tumours that progressed after long responses to targeted therapy.

This is mechanistic and preclinical evidence. There is no approved way to suppress APOBEC activity clinically, and a high APOBEC signature is not currently an actionable biomarker.

Why It Still Matters Without Being Actionable

Even though a high APOBEC signature does not currently select a therapy, it carries interpretive value. It flags a tumour that is actively diversifying, which affects how much confidence to place in a single biopsy and raises the prior probability that resistance will emerge through newly acquired mutations rather than pre-existing clones.

APOBEC-associated mutations also disproportionately generate potential neoantigens, so the process is part of why some heavily mutated tumours are immunogenic. Trials of agents that exploit the replication stress APOBEC creates, such as ATR inhibitors, keep it a plausible future target.

Key Takeaways

• ·APOBEC3 enzymes deaminate cytidine in single-stranded DNA, producing TpC-context mutation clusters.
• ·The signature is often subclonal, so APOBEC drives continuing intratumour heterogeneity.
• ·APOBEC has been linked to therapy resistance in models but is not yet a clinical biomarker.