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dc.contributor.authorWhitworth, James
dc.contributor.authorSmith, Philip S
dc.contributor.authorMartin, Jose-Ezequiel
dc.contributor.authorWest, Hannah
dc.contributor.authorLuchetti, Andrea
dc.contributor.authorRodger, Faye
dc.contributor.authorClark, Graeme
dc.contributor.authorCarss, Keren
dc.contributor.authorStephens, Jonathan
dc.contributor.authorStirrups, Kathleen
dc.contributor.authorPenkett, Chris
dc.contributor.authorMapeta, Rutendo
dc.contributor.authorAshford, Sofie
dc.contributor.authorMegy, Karyn
dc.contributor.authorShakeel, Hassan
dc.contributor.authorAhmed, Munaza
dc.contributor.authorAdlard, Julian
dc.contributor.authorBarwell, Julian
dc.contributor.authorBrewer, Carole
dc.contributor.authorCasey, Ruth T
dc.contributor.authorArmstrong, Ruth
dc.contributor.authorCole, Trevor
dc.contributor.authorEvans, Dafydd Gareth
dc.contributor.authorFostira, Florentia
dc.contributor.authorGreenhalgh, Lynn
dc.contributor.authorHanson, Helen
dc.contributor.authorHenderson, Alex
dc.contributor.authorHoffman, Jonathan
dc.contributor.authorIzatt, Louise
dc.contributor.authorKumar, Ajith
dc.contributor.authorKwong, Ava
dc.contributor.authorLalloo, Fiona
dc.contributor.authorOng, Kai Ren
dc.contributor.authorPaterson, Joan
dc.contributor.authorPark, Soo-Mi
dc.contributor.authorChen-Shtoyerman, Rakefet
dc.contributor.authorSearle, Claire
dc.contributor.authorSide, Lucy
dc.contributor.authorSkytte, Anne-Bine
dc.contributor.authorSnape, Katie
dc.contributor.authorWoodward, Emma R
dc.contributor.authorNIHR BioResource Rare Diseases Consortium
dc.contributor.authorTischkowitz, Marc D
dc.contributor.authorMaher, Eamonn R
dc.date.accessioned2018-08-16T17:14:35Z
dc.date.available2018-08-16T17:14:35Z
dc.date.issued2018-07-05
dc.identifier.issn0002-9297
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/278910
dc.description.abstractMultiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.
dc.description.sponsorshipJW is supported by a Cancer Research UK Cambridge Cancer Centre Clinical Research Training Fellowship. Funding for the NIHR BioResource – Rare diseases project was provided by the National Institute for Health Research (NIHR, grant number RG65966). ERM acknowledges support from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), Cancer Research UK Cambridge Cancer Centre and Medical Research Council Infrastructure Award. The University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. DGE is an NIHR Senior Investigator and is supported by the all Manchester NIHR Biomedical Research Centre.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherElsevier BV
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectNIHR BioResource Rare Diseases Consortium
dc.subjectHumans
dc.subjectNeoplasms, Multiple Primary
dc.subjectGenetic Predisposition to Disease
dc.subjectPhenotype
dc.subjectGerm-Line Mutation
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectGenetic Variation
dc.subjectGenetic Testing
dc.subjectBiomarkers, Tumor
dc.titleComprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.
dc.typeArticle
prism.endingPage18
prism.issueIdentifier1
prism.publicationDate2018
prism.publicationNameAm J Hum Genet
prism.startingPage3
prism.volume103
dc.identifier.doi10.17863/CAM.26291
dcterms.dateAccepted2018-04-25
rioxxterms.versionofrecord10.1016/j.ajhg.2018.04.013
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-07
dc.contributor.orcidWhitworth, James [0000-0002-3682-2298]
dc.contributor.orcidSmith, Philip [0000-0002-9306-1747]
dc.contributor.orcidMaher, Eamonn [0000-0002-6226-6918]
dc.identifier.eissn1537-6605
rioxxterms.typeJournal Article/Review
pubs.funder-project-idEuropean Research Council (323004)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (NF-SI-0616-10035)
pubs.funder-project-idCancer Research UK (C20/A20917)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (BRC 2012-2017)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (BRC 2012-2017)
cam.issuedOnline2018-06-14


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International