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/

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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 associated with worse clinical outcomes (e.g., relapse risk and survival).
- Trunk (clonal) mutations show positive selection (dN/dS > 1) while branch (subclonal) mutations show purifying selection (dN/dS < 1); overall late-stage evolution tends toward neut
- The study analyzes multiple cohorts (ALL, CLL, ER-positive breast cancer, urothelial bladder cancer, glioblastoma) and validates with an original multiple myeloma cohort (624 patie

QC result: Pass.