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dc.contributor.authorSmith, Philip S
dc.contributor.authorWest, Hannah
dc.contributor.authorWhitworth, James
dc.contributor.authorCastle, Bruce
dc.contributor.authorSansbury, Francis H
dc.contributor.authorWarren, Anne Y
dc.contributor.authorWoodward, Emma R
dc.contributor.authorTischkowitz, Marc
dc.contributor.authorMaher, Eamonn R
dc.date.accessioned2020-09-10T23:30:51Z
dc.date.available2020-09-10T23:30:51Z
dc.date.issued2021-01
dc.identifier.issn1045-2257
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/310142
dc.description.abstractInherited renal cell carcinoma (RCC) is associated with multiple familial cancer syndromes but most individuals with features of non-syndromic inherited RCC do not harbor variants in the most commonly tested renal cancer predisposition genes (CPGs). We investigated whether undiagnosed cases might harbor mutations in CPGs that are not routinely tested for by testing 118 individuals with features suggestive of inherited RCC (family history of RCC, two or more primary RCC aged <60 years, or early onset RCC ≤46 years) for the presence of pathogenic variants in a large panel of CPGs. All individuals had been prescreened for pathogenic variants in the major RCC genes. We detected pathogenic or likely pathogenic (P/LP) variants of potential clinical relevance in 16.1% (19/118) of individuals, including P/LP variants in BRIP1 (n = 4), CHEK2 (n = 3), MITF (n = 1), and BRCA1 (n = 1). Though the power to detect rare variants was limited by sample size the frequency of truncating variants in BRIP1, 4/118, was significantly higher than in controls (P = 5.92E-03). These findings suggest that the application of genetic testing for larger inherited cancer gene panels in patients with indicators of a potential inherited RCC can increase the diagnostic yield for P/LP variants. However, the clinical utility of such a diagnostic strategy requires validation and further evaluation and in particular, confirmation of rarer RCC genotype-phenotype associations is required.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherWiley
dc.rightsAll rights reserved
dc.subjectHumans
dc.subjectCarcinoma, Renal Cell
dc.subjectKidney Neoplasms
dc.subjectRNA Helicases
dc.subjectBRCA1 Protein
dc.subjectGenetic Heterogeneity
dc.subjectGerm-Line Mutation
dc.subjectAdolescent
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectChild
dc.subjectFemale
dc.subjectMale
dc.subjectMicrophthalmia-Associated Transcription Factor
dc.subjectFanconi Anemia Complementation Group Proteins
dc.subjectGenetic Testing
dc.subjectCheckpoint Kinase 2
dc.titlePathogenic germline variants in patients with features of hereditary renal cell carcinoma: Evidence for further locus heterogeneity.
dc.typeArticle
prism.endingPage16
prism.issueIdentifier1
prism.publicationDate2021
prism.publicationNameGenes Chromosomes Cancer
prism.startingPage5
prism.volume60
dc.identifier.doi10.17863/CAM.57227
dcterms.dateAccepted2020-08-19
rioxxterms.versionofrecord10.1002/gcc.22893
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2021-01
dc.contributor.orcidSmith, Philip S [0000-0002-9306-1747]
dc.contributor.orcidWhitworth, James [0000-0002-3682-2298]
dc.contributor.orcidSansbury, Francis H [0000-0002-5048-3309]
dc.contributor.orcidWoodward, Emma R [0000-0002-6297-2855]
dc.contributor.orcidTischkowitz, Marc [0000-0002-7880-0628]
dc.contributor.orcidMaher, Eamonn R [0000-0002-6226-6918]
dc.identifier.eissn1098-2264
rioxxterms.typeJournal Article/Review
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (BRC 2012-2017)
pubs.funder-project-idCancer Research UK (C20/A20917)
cam.issuedOnline2020-09-19
cam.orpheus.successMon Sep 14 09:22:26 BST 2020 - Embargo updated
rioxxterms.freetoread.startdate2021-08-23


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