105: When Tumors Go Neutral: Genome-Level Selection and Resistance

Persi E et al., Nature Communications - This episode unpacks a multi-cohort study showing that tumors evolving toward neutral genome-level selection (dN/dS ≈ 1) during or after therapy are associated with treatment resistance and poorer outcomes. Key terms: tumor evolution, dN/dS, neutral evolution, treatment resistance, whole-exome sequencing. Study Highlights:The authors analyzed paired whole-exome data from multiple untreated and treated cancer cohorts and an original 624-patient multiple myeloma cohort to estimate genome-level dN/dS and track evolution. In untreated primary progression dN/dS is largely stable per patient, with some cancer-specific shifts during metastasis. In diverse treated, resistant tumors there is a near-universal shift toward neutral evolution (dN/dS ≈ 1), and this shift correlates with worse clinical outcomes. Phylogenetic analysis shows positive selection on trunk/clonal mutations and purifying selection on branch/subclonal mutations, producing an overall neutral regime in late stages. Conclusion:Serial measurement of genome-level dN/dS can flag emerging treatment resistance: a shift toward neutrality indicates higher tumor fitness and poorer prognosis and may prompt therapy reassessment. Music:Enjoy the music based on this article at the end of the episode. Article title:Genome-level selection in tumors as a universal marker of resistance to therapy First author:Persi E Journal:Nature Communications DOI:10.1038/s41467-025-61709-x Reference:Persi E., Sudalagunta P.R., Wolf Y.I., Canevarolo R.R., Damaghi M., Shain K.H., Silva A.S., Koonin E.V., Genome-level selection in tumors as a universal marker of resistance to therapy. Nature Communications (2025). DOI: 10.1038/s41467-025-61709-x License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/genome-level-selection-resistance-therapy QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-13. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript's core scientific claims about genome-wide dN/dS, treatment effects, neutral evolution, trunk vs. branch selection, datasets and methods, and clinical implications, plus acknowledged limitations and potential mechanisms (epigenetics, hypermutators).- transcript topics: Genome-wide dN/dS metric; Untreated cancer evolution; Treated cancer evolution and neutrality; Trunk vs branch selection in tumor phylogenies; Cohorts and methods (WES, MM cohort); Clinical implications and prognosis QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 7- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- dN/dS is used as a genome-wide measure of selection strength in tumor genomes.- In untreated cancers, dN/dS within a patient remains stable during primary progression, with cancer-specific signatures emerging in metastasis.- In diverse treated cancers, there is a universal shift toward neutral evolution (dN/dS approximately 1).- Post-treatment neutrality is as... Chapters (00:00:14) - How do we learn how tumors evolve?(00:04:09) - Tumor fitness and the science(00:07:03) - The Nature of breast cancer(00:08:36) - DNDs in breast cancer(00:09:34) - Neutral evolution in leukemias(00:11:14) - Multiple myeloma evolution: neutral or(00:13:58) - A new biomarker for cancer treatment failure