{"entity":{"id":"paper-mcfarland-proc-natl-acad-sci-u-s-a","kind":"paper","name":"Impact of deleterious passenger mutations on cancer progression","aka":[],"tldr":"Paper cited by one term page, indexed on Europe PMC as PubMed record 23388632 and published in Proceedings of the National Academy of Sciences; the citing page links this DOI, which is how the record was matched.","summary":"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.\n\nIndexed on Europe PMC as PubMed record 23388632 (DOI 10.1073/pnas.1213968110). Matched by DOI alone: one term page cites this DOI among its external links (the pages are listed under Related), and this page was written so that the citation resolves inside OnCo. No figure has been checked by an editor.","asOf":"2026-09-22","links":[{"label":"Proc Natl Acad Sci U S A 2013","url":"https://doi.org/10.1073/pnas.1213968110"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/23388632/"},{"label":"Europe PMC","url":"https://europepmc.org/article/MED/23388632"}],"tags":["europepmc-ingest"],"related":["driver-passenger-model"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["pnas"],"dependsOn":[],"notes":[],"journal":"Proceedings of the National Academy of Sciences","year":2013,"doi":"10.1073/pnas.1213968110","pmid":"23388632","authors":"McFarland CD, Korolev KS, Kryukov GV, et al.","paperType":"observational","findings":[],"whatItMeans":"One term page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.","caveats":["Matched to the citing OnCo records by DOI alone; the summary reproduces the Europe PMC abstract and no figure has been verified against the full paper."]},"route":"/key-papers/paper-mcfarland-proc-natl-acad-sci-u-s-a/","neighbours":{"term":[{"id":"driver-passenger-model","kind":"term","name":"Driver and passenger mutations: the refined somatic mutation theory","route":"/terms/driver-passenger-model/"}],"journal":[{"id":"pnas","kind":"journal","name":"Proceedings of the National Academy of Sciences","route":"/journals/pnas/"}]}}