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dc.contributor.authorAbelson, Sagien
dc.contributor.authorCollord, Graceen
dc.contributor.authorNg, Stanley WKen
dc.contributor.authorWeissbrod, Omeren
dc.contributor.authorMendelson Cohen, Nettaen
dc.contributor.authorNiemeyer, Elisabethen
dc.contributor.authorBarda, Noamen
dc.contributor.authorZuzarte, Philip Cen
dc.contributor.authorHeisler, Lawrenceen
dc.contributor.authorSundaravadanam, Yogien
dc.contributor.authorLuben, Roberten
dc.contributor.authorHayat, Shabinaen
dc.contributor.authorWang, Ting Tingen
dc.contributor.authorZhao, Zhenen
dc.contributor.authorCirlan, Iuliaen
dc.contributor.authorPugh, Trevor Jen
dc.contributor.authorSoave, Daviden
dc.contributor.authorNg, Karenen
dc.contributor.authorLatimer, Callien
dc.contributor.authorHardy, Claireen
dc.contributor.authorRaine, Keiranen
dc.contributor.authorJones, Daviden
dc.contributor.authorHoult, Dianaen
dc.contributor.authorBritten, Abigailen
dc.contributor.authorMcPherson, John Den
dc.contributor.authorJohansson, Mattiasen
dc.contributor.authorMbabaali, Faridahen
dc.contributor.authorEagles, Jennaen
dc.contributor.authorMiller, Jessica Ken
dc.contributor.authorPasternack, Danielleen
dc.contributor.authorTimms, Leeen
dc.contributor.authorKrzyzanowski, Paulen
dc.contributor.authorAwadalla, Philipen
dc.contributor.authorCosta, Ruien
dc.contributor.authorSegal, Eranen
dc.contributor.authorBratman, Scott Ven
dc.contributor.authorBeer, Philipen
dc.contributor.authorBehjati, Samen
dc.contributor.authorMartincorena, Inigoen
dc.contributor.authorWang, Jean CYen
dc.contributor.authorBowles, Kristian Men
dc.contributor.authorQuirós, J Ramónen
dc.contributor.authorKarakatsani, Annaen
dc.contributor.authorLa Vecchia, Carloen
dc.contributor.authorTrichopoulou, Antoniaen
dc.contributor.authorSalamanca-Fernández, Elenaen
dc.contributor.authorHuerta, José Men
dc.contributor.authorBarricarte, Aurelioen
dc.contributor.authorTravis, Ruth Cen
dc.contributor.authorTumino, Rosarioen
dc.contributor.authorMasala, Giovannaen
dc.contributor.authorBoeing, Heineren
dc.contributor.authorPanico, Salvatoreen
dc.contributor.authorKaaks, Rudolfen
dc.contributor.authorKrämer, Alwinen
dc.contributor.authorSieri, Sabinaen
dc.contributor.authorRiboli, Elioen
dc.contributor.authorVineis, Paoloen
dc.contributor.authorFoll, Matthieuen
dc.contributor.authorMcKay, Jamesen
dc.contributor.authorPolidoro, Silviaen
dc.contributor.authorSala, Núriaen
dc.contributor.authorKhaw, Kay-Teeen
dc.contributor.authorVermeulen, Roelen
dc.contributor.authorCampbell, Peter Jen
dc.contributor.authorPapaemmanuil, Ellien
dc.contributor.authorMinden, Mark Den
dc.contributor.authorTanay, Amosen
dc.contributor.authorBalicer, Ran Den
dc.contributor.authorWareham, Nicholasen
dc.contributor.authorGerstung, Moritzen
dc.contributor.authorDick, John Een
dc.contributor.authorBrennan, Paulen
dc.contributor.authorVassiliou, Georgeen
dc.contributor.authorShlush, Liran Ien
dc.date.accessioned2018-10-03T04:43:38Z
dc.date.available2018-10-03T04:43:38Z
dc.date.issued2018-07-19en
dc.identifier.issn0028-0836
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/283029
dc.description.abstractThe incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure1. The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukaemic haematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion2,3. However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis (ARCH)4-8. Here we use deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH. We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis (pre-AML group), together with 414 unselected age- and gender-matched individuals (control group). Pre-AML cases were distinct from controls and had more mutations per sample, higher variant allele frequencies, indicating greater clonal expansion, and showed enrichment of mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival; this model was validated in an independent cohort of 29 pre-AML cases and 262 controls. Because AML is rare, we also developed an AML predictive model using a large electronic health record database that identified individuals at greater risk. Collectively our findings provide proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation. This could in future enable earlier detection and monitoring, and may help to inform intervention.
dc.languageengen
dc.publisherNature Research
dc.subjectAdulten
dc.subjectAge Factorsen
dc.subjectAgeden
dc.subjectDisease Progressionen
dc.subjectElectronic Health Recordsen
dc.subjectFemaleen
dc.subjectGenetic Predisposition to Diseaseen
dc.subjectHealthen
dc.subjectHumansen
dc.subjectLeukemia, Myeloid, Acuteen
dc.subjectMaleen
dc.subjectMiddle Ageden
dc.subjectModels, Geneticen
dc.subjectMutagenesisen
dc.subjectMutationen
dc.subjectPrevalenceen
dc.subjectRisk Assessmenten
dc.titlePrediction of acute myeloid leukaemia risk in healthy individualsen
dc.typeArticle
prism.endingPage404
prism.issueIdentifier7714en
prism.publicationDate2018en
prism.publicationNameNatureen
prism.startingPage400
prism.volume559en
dc.identifier.doi10.17863/CAM.30393
dcterms.dateAccepted2018-05-03en
rioxxterms.versionofrecord10.1038/s41586-018-0317-6en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2018-07-19en
dc.contributor.orcidCollord, Grace [0000-0003-1924-4411]
dc.contributor.orcidLuben, Robert [0000-0002-5088-6343]
dc.contributor.orcidKhaw, Kay-Tee [0000-0002-8802-2903]
dc.contributor.orcidWareham, Nicholas [0000-0003-1422-2993]
dc.contributor.orcidVassiliou, George [0000-0003-4337-8022]
dc.identifier.eissn1476-4687
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MC_UU_12015/1)
pubs.funder-project-idMRC (MC_PC_13048)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (NF-SI-0512-10135)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (NF-SI-0617-10149)
pubs.funder-project-idMRC (G0401527)
pubs.funder-project-idMRC (G1000143)
pubs.funder-project-idMRC (MC_PC_12009)
pubs.funder-project-idMEDICAL RESEARCH COUNCIL (MR/N003284/1)
cam.issuedOnline2018-07-09en
rioxxterms.freetoread.startdate2019-07-09


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