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dc.contributor.authorZapata, L
dc.contributor.authorPich, O
dc.contributor.authorSerrano, L
dc.contributor.authorKondrashov, FA
dc.contributor.authorOssowski, S
dc.contributor.authorSchaefer, MH
dc.coverage.spatialEngland
dc.date.accessioned2023-07-05T12:47:22Z
dc.date.available2023-07-05T12:47:22Z
dc.date.issued2018-05-31
dc.identifierARTN 67
dc.identifier10.1186/s13059-018-1434-0
dc.identifier.citationGenome Biology, 2018, 19 (1), pp. 67 -en_US
dc.identifier.issn1474-7596
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5877
dc.identifier.eissn1474-760X
dc.identifier.eissn1474-760X
dc.identifier.doi10.1186/s13059-018-1434-0
dc.description.abstractBACKGROUND: Natural selection shapes cancer genomes. Previous studies used signatures of positive selection to identify genes driving malignant transformation. However, the contribution of negative selection against somatic mutations that affect essential tumor functions or specific domains remains a controversial topic. RESULTS: Here, we analyze 7546 individual exomes from 26 tumor types from TCGA data to explore the portion of the cancer exome under negative selection. Although we find most of the genes neutrally evolving in a pan-cancer framework, we identify essential cancer genes and immune-exposed protein regions under significant negative selection. Moreover, our simulations suggest that the amount of negative selection is underestimated. We therefore choose an empirical approach to identify genes, functions, and protein regions under negative selection. We find that expression and mutation status of negatively selected genes is indicative of patient survival. Processes that are most strongly conserved are those that play fundamental cellular roles such as protein synthesis, glucose metabolism, and molecular transport. Intriguingly, we observe strong signals of selection in the immunopeptidome and proteins controlling peptide exposition, highlighting the importance of immune surveillance evasion. Additionally, tumor type-specific immune activity correlates with the strength of negative selection on human epitopes. CONCLUSIONS: In summary, our results show that negative selection is a hallmark of cell essentiality and immune response in cancer. The functional domains identified could be exploited therapeutically, ultimately allowing for the development of novel cancer treatments.
dc.formatElectronic
dc.format.extent67 -
dc.languageeng
dc.language.isoengen_US
dc.publisherBMCen_US
dc.relation.ispartofGenome Biology
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectCancer immunology
dc.subjectCancer-essential genes
dc.subjectNegative selection
dc.subjectNeoepitopes
dc.subjectTumor evolution
dc.subjectAntigens, Neoplasm
dc.subjectExome
dc.subjectGenes, Neoplasm
dc.subjectGenome
dc.subjectHumans
dc.subjectNeoplasms
dc.subjectPeptides
dc.subjectSelection, Genetic
dc.titleNegative selection in tumor genome evolution acts on essential cellular functions and the immunopeptidome.en_US
dc.typeJournal Article
dcterms.dateAccepted2018-04-20
dc.date.updated2023-07-05T12:46:56Z
rioxxterms.versionVoRen_US
rioxxterms.versionofrecord10.1186/s13059-018-1434-0en_US
rioxxterms.licenseref.startdate2018-05-31
rioxxterms.typeJournal Article/Reviewen_US
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/29855388
pubs.issue1
pubs.organisational-group/ICR
pubs.publication-statusPublished online
pubs.publisher-urlhttp://dx.doi.org/10.1186/s13059-018-1434-0
pubs.volume19
icr.researchteamDirectorate for CECen_US
dc.contributor.icrauthorZapata Ortiz, Luis
icr.provenanceDeposited by Mr Arek Surman (impersonating Dr Luis Zapata Ortiz) on 2023-07-05. Deposit type is initial. No. of files: 1. Files: Negative selection in tumor genome evolution acts on essential cellular functions and the immunopeptidome.pdf


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