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dc.contributor.authorGagliardi, Amedeo
dc.contributor.authorDugué, Pierre-Antoine
dc.contributor.authorNøst, Therese Haugdahl
dc.contributor.authorSouthey, Melissa C.
dc.contributor.authorBuchanan, Daniel D.
dc.contributor.authorSchmidt, Daniel F
dc.contributor.authorMakalic, Enes
dc.contributor.authorHodge, Allison M
dc.contributor.authorEnglish, Dallas R.
dc.contributor.authorWong Doo, Nicole
dc.contributor.authorHopper, John L.
dc.contributor.authorSeveri, Gianluca
dc.contributor.authorBaglietto, Laura
dc.contributor.authorNaccarati, Alessio
dc.contributor.authorKrogh, Vittorio
dc.contributor.authorPalli, Domenico
dc.contributor.authorPanico, Salvatore
dc.contributor.authorSacerdote, Carlotta
dc.contributor.authorTumino, Rosario
dc.contributor.authorLund, Eiliv
dc.contributor.authorGiles, Graham
dc.contributor.authorPardini, Barbara
dc.contributor.authorSandanger, Torkjel M
dc.contributor.authorMilne, Roger L.
dc.contributor.authorPaolo, Vineis
dc.contributor.authorPolidoro, Silvia
dc.contributor.authorFiorito, Giovanni
dc.date.accessioned2021-03-30T20:46:13Z
dc.date.available2021-03-30T20:46:13Z
dc.date.issued2020-08-11
dc.description.abstract<p>Background: Age-related epigenetic dysregulations are associated with several diseases, including cancer. The number of stochastic epigenetic mutations (SEM) has been suggested as a biomarker of life-course accumulation of exposure-related DNA damage; however, the predictive role of SEMs in cancer has seldom been investigated. <p>Methods: A SEM, at a given CpG site, was defined as an extreme outlier of DNA methylation value distribution across individuals. We investigated the association of the total number of SEMs with the risk of eight cancers in 4,497 case–control pairs nested in three prospective cohorts. Furthermore, we investigated whether SEMs were randomly distributed across the genome or enriched in functional genomic regions. <p>Results: In the three-study meta-analysis, the estimated ORs per one-unit increase in log(SEM) from logistic regression models adjusted for age and cancer risk factors were 1.25; 95% confidence interval (CI), 1.11–1.41 for breast cancer, and 1.23; 95% CI, 1.07–1.42 for lung cancer. In the Melbourne Collaborative Cohort Study, the OR for mature B-cell neoplasm was 1.46; 95% CI, 1.25–1.71. Enrichment analyses indicated that SEMs frequently occur in silenced genomic regions and in transcription factor binding sites regulated by EZH2 and SUZ12 (P < 0.0001 and P = 0.0005, respectively): two components of the polycomb repressive complex 2 (PCR2). Finally, we showed that PCR2-specific SEMs are generally more stable over time compared with SEMs occurring in the whole genome. <p>Conclusions: The number of SEMs is associated with a higher risk of different cancers in prediagnostic blood samples. <p>Impact: We identified a candidate biomarker for cancer early detection, and we described a carcinogenesis mechanism involving PCR2 complex proteins worthy of further investigations.en_US
dc.identifier.citationGagliardi, Dugué, Nøst, Southey, Buchanan, Schmidt, Makalic, Hodge, English, Wong Doo, Hopper, Severi, Baglietto, Naccarati, Krogh, Palli, Panico, Sacerdote, Tumino, Lund, Giles, Pardini, Sandanger, Milne, Paolo, Polidoro, Fiorito. Stochastic Epigenetic Mutations Are Associated with Risk of Breast Cancer, Lung Cancer, and Mature B-cell Neoplasms. Cancer Epidemiology, Biomarkers and Prevention. 2020en_US
dc.identifier.cristinIDFRIDAID 1861300
dc.identifier.doi10.1158/1055-9965.EPI-20-0451
dc.identifier.issn1055-9965
dc.identifier.issn1538-7755
dc.identifier.urihttps://hdl.handle.net/10037/20759
dc.language.isoengen_US
dc.publisherAmerican Association for Cancer Researchen_US
dc.relation.journalCancer Epidemiology, Biomarkers and Prevention
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/308610/EU/Enhanced exposure assessment and omic profiling for high priority environmental exposures in Europe/EXPOSOMICS/en_US
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2020 The Author(s)en_US
dc.subjectVDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762en_US
dc.subjectVDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762en_US
dc.titleStochastic Epigenetic Mutations Are Associated with Risk of Breast Cancer, Lung Cancer, and Mature B-cell Neoplasmsen_US
dc.type.versionsubmittedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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