Punctuated mutagenesis promotes multi-step evolutionary adaptation in human cancers.

Punctuated mutagenesis significantly enhances tumor cells' ability to cross fitness valleys, promoting multi-step adaptation in human cancers.

• Why it matters: Understanding how non-gradual mutagenesis influences cancer evolution is crucial because it may explain mechanisms behind rapid tumor adaptation and resistance, filling gaps left by models of gradual mutation accumulation.
• What they did: The study analyzed how episodic bursts of mutagenesis, particularly APOBEC signatures, increase the likelihood of multiple mutations occurring in close succession, facilitating crossing fitness valleys in tumor evolution, using data from The Cancer Genome Atlas.
• The result: Findings suggest that tumors with APOBEC mutagenesis signatures exhibit higher rates of crossing fitness valleys, which may improve their overall adaptability despite the limiting effects of clonal interference.