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Despite forays into the description and quantification of these punctuated events, the effects of such changes on subsequent cancer evolution remain incompletely understood. Here we investigate how non-gradual mutagenesis affects the ability of tumor cells to acquire and retain fitness-enhancing adaptations. We find that punctuated mutagenesis significantly facilitates adaptation in scenarios where adaptation requires crossing a fitness valley, that is when multiple mutations are required which individually are maladaptive but jointly confer a fitness advantage. By increasing the probability that multiple mutations occur in close succession, punctuation increases the chance that mutants in a fitness valley mutate further to reach a fitness peak before going extinct. Analyzing data from The Cancer Genome Atlas, we find that tumors with signatures of APOBEC mutagenesis, which has been shown to proceed in episodic bursts, exhibit patterns consistent with higher rates of crossing fitness valleys. Lastly, we characterize how the interplay between this enhanced ability to cross fitness valleys and adaptation-limiting effects of clonal interference affects overall adaptability in complex fitness landscapes.<\/jats:p>","DOI":"10.7554\/elife.108058","type":"journal-article","created":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T15:31:32Z","timestamp":1759419092000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.108058","source":"Crossref","is-referenced-by-count":0,"title":["Punctuated mutagenesis promotes multi-step evolutionary adaptation in human cancers"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8552-7767","authenticated-orcid":true,"given":"Christopher J","family":"Graser","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02jzgtq86","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Data Science, Dana-Farber Cancer Institute","place":["Boston, United States"]},{"id":[{"id":"https:\/\/ror.org\/03vek6s52","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biostatistics, Harvard T.H. 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