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dc.contributor.authorWhitworth, Jamesen
dc.contributor.authorSmith, Philipen
dc.contributor.authorMartin, Jose-Ezequielen
dc.contributor.authorWest, Hannahen
dc.contributor.authorLuchetti, Andreaen
dc.contributor.authorRodger, Fayeen
dc.contributor.authorClark, Graemeen
dc.contributor.authorCarss, Kerenen
dc.contributor.authorStephens, Jonathanen
dc.contributor.authorStirrups, Kathleenen
dc.contributor.authorPenkett, Chrisen
dc.contributor.authorMapeta, Rutendoen
dc.contributor.authorAshford, Sofieen
dc.contributor.authorMegy, Karynen
dc.contributor.authorShakeel, Hassanen
dc.contributor.authorAhmed, Munazaen
dc.contributor.authorAdlard, Julianen
dc.contributor.authorBarwell, Julianen
dc.contributor.authorBrewer, Caroleen
dc.contributor.authorCasey, Ruthen
dc.contributor.authorArmstrong, Ruthen
dc.contributor.authorCole, Trevoren
dc.contributor.authorEvans, Dafydd Garethen
dc.contributor.authorFostira, Florentiaen
dc.contributor.authorGreenhalgh, Lynnen
dc.contributor.authorHanson, Helenen
dc.contributor.authorHenderson, Alexen
dc.contributor.authorHoffman, Jonathanen
dc.contributor.authorIzatt, Louiseen
dc.contributor.authorKumar, Ajithen
dc.contributor.authorKwong, Avaen
dc.contributor.authorLalloo, Fionaen
dc.contributor.authorOng, Kai Renen
dc.contributor.authorPaterson, Joanen
dc.contributor.authorPark, Soo-Mien
dc.contributor.authorChen-Shtoyerman, Rakefeten
dc.contributor.authorSearle, Claireen
dc.contributor.authorSide, Lucyen
dc.contributor.authorSkytte, Anne-Bineen
dc.contributor.authorSnape, Katieen
dc.contributor.authorWoodward, Emma Ren
dc.contributor.authorNIHR BioResource Rare Diseases Consortium,en
dc.contributor.authorTischkowitz, Marc Den
dc.contributor.authorMaher, Eamonn Ren
dc.description.abstractMultiple primary tumors (MPT) affect a substantial proportion of cancer survivors and may result from various causes including inherited predisposition. Currently, germline genetic testing of MPT cases for cancer predisposition gene (CPG) variants is mostly targeted by tumor type. We ascertained pre-assessed MPT cases from genetics centers (defined as ≥2 primaries by age 60 years or ≥3 by 70) and performed whole genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment/molecular investigations, pathogenic variants in moderate and high-risk CPGs were detected in 67/440 (15.2%) of probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies including structural variants at low frequency (6/440 (1.4%) of 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 a control population (χ2=43.642 P=<0.0001). 2/67 (3%) of probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Summing together variant detection rates from a similarly ascertained previous MPT case series, the present results suggest that first-line comprehensive CPG analysis in a clinical genetics referral-based MPT cohort would detect a deleterious variant in about a third of cases.
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.publisherUniversity of Chicago Press
dc.rightsAttribution 4.0 International*
dc.subjectNIHR BioResource Rare Diseases Consortiumen
dc.subjectNeoplasms, Multiple Primaryen
dc.subjectGenetic Predisposition to Diseaseen
dc.subjectGerm-Line Mutationen
dc.subjectMiddle Ageden
dc.subjectGenetic Variationen
dc.subjectGenetic Testingen
dc.subjectBiomarkers, Tumoren
dc.titleComprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.en
prism.publicationNameAmerican journal of human geneticsen
dc.contributor.orcidWhitworth, James [0000-0002-3682-2298]
dc.contributor.orcidSmith, Philip [0000-0002-9306-1747]
dc.contributor.orcidKwong, Ava [0000-0002-6968-9489]
dc.contributor.orcidSkytte, Anne-Bine [0000-0002-0067-9557]
rioxxterms.typeJournal Article/Reviewen
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)

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