ArticleProceedings of the National Academy of Sciences of the United States of America2013
Impact of deleterious passenger mutations on cancer progression.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 173 papers, 1 of them a synthesis that pooled it.
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Who cites it
173 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Prognostic significance of POLE proofreading mutations in endometrial cancer.Journal of the National Cancer Institute · 2015Pooled it
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- Global Geo-Pharmacogenomics: Environmental Mutational Signatures Drive Population-Level Heterogeneity in Anticancer Drug Response.Journal of xenobiotics · 2026Article
- Linking somatic mutations in cancer to the electronic properties of DNA.BMC genomics · 2026Article
- Interpreting cancer genetics through a two-step "evolutionary cascade hypothesis": bridging neutral and selective perspectives.Journal of translational medicine · 2026Review
- Aging represses oncogenic KRAS-driven lung tumorigenesis and alters tumor suppression.Nature aging · 2025Article
- Comprehensive Analysis of Human Colorectal Cancers Harboring Polymerase Epsilon Mutations.International journal of molecular sciences · 2025Article
- Genome-level selection in tumors as a universal marker of resistance to therapy.Nature communications · 2025Article
- Biophysical Properties of Somatic Cancer Mutations in the S4 Transmembrane Segment of the Human Voltage-Gated Proton Channel hHBiomolecules · 2025Article
- Oncometabolites at the crossroads of genetic, epigenetic and ecological alterations in cancer.Cell death and differentiation · 2024Review
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- Spontaneous single-nucleotide substitutions and microsatellite mutations have distinct distributions of fitness effects.PLoS biology · 2024Article
- Non-Poissonian Bursts in the Arrival of Phenotypic Variation Can Strongly Affect the Dynamics of Adaptation.Molecular biology and evolution · 2024Article
- Synergistic epistasis among cancer drivers can rescue early tumors from the accumulation of deleterious passengers.PLoS computational biology · 2024Article
- A dynamical limit to evolutionary adaptation.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Plasminogen missense variants and their involvement in cardiovascular and inflammatory disease.Frontiers in cardiovascular medicine · 2024Review
- A multiscale model of the role of microenvironmental factors in cell segregation and heterogeneity in breast cancer development.PLoS computational biology · 2023Article
- Reuniting philosophy and science to advance cancer research.Biological reviews of the Cambridge Philosophical Society · 2023Article
- A dynamical limit to evolutionary adaptation.bioRxiv : the preprint server for biology · 2023Article
113 more citing papers are in PubMed but not listed here.
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5 authors.
Funding
Abstract
Cancer progression is driven by the accumulation of a small number of genetic alterations. However, these few driver alterations reside in a cancer genome alongside tens of thousands of additional mutations termed passengers. Passengers are widely believed to have no role in cancer, yet many passengers fall within protein-coding genes and other functional elements that can have potentially deleterious effects on cancer cells. Here we investigate the potential of moderately deleterious passengers to accumulate and alter the course of neoplastic progression. Our approach combines evolutionary simulations of cancer progression with an analysis of cancer sequencing data. From simulations, we find that passengers accumulate and largely evade natural selection during progression. Although individually weak, the collective burden of passengers alters the course of progression, leading to several oncological phenomena that are hard to explain with a traditional driver-centric view. We then tested the predictions of our model using cancer genomics data and confirmed that many passengers are likely damaging and have largely evaded negative selection. Finally, we use our model to explore cancer treatments that exploit the load of passengers by either (i) increasing the mutation rate or (ii) exacerbating their deleterious effects. Though both approaches lead to cancer regression, the latter is a more effective therapy. Our results suggest a unique framework for understanding cancer progression as a balance of driver and passenger mutations.
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