Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases

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dc.contributor.authorYngvadottir, Bryndis
dc.contributor.authorAndreou, Avgi
dc.contributor.authorBassaganyas, Laia
dc.contributor.authorLarionov, Alexey
dc.contributor.authorCornish, Alex J.
dc.contributor.authorChubb, Daniel
dc.contributor.authorSaunders, Charlie N.
dc.contributor.authorSmith, Philip S.
dc.contributor.authorZhang, Huairen
dc.contributor.authorCole, Yasemin
dc.contributor.authorGenomics England Research Consortium
dc.contributor.authorLarkin, James
dc.contributor.authorBrowning, Lisa
dc.contributor.authorTurajlic, Samra
dc.contributor.authorLitchfield, Kevin
dc.contributor.authorHoulston, Richard S.
dc.contributor.authorMaher, Eamonn R.
dc.date.accessioned2022-06-10T13:46:07Z
dc.date.available2022-06-10T13:46:07Z
dc.date.issued2022-04-20
dc.description.abstractBackground Renal cell carcinoma (RCC) occurs in a number of cancer predisposition syndromes but the genetic architecture of susceptibility to RCC is not well defined. We investigated the frequency of pathogenic germline variants in cancer susceptibility genes (CSGs) within a large series of unselected RCC participants. Methods Whole genome sequencing data on 1336 RCC participants and 5834 controls recruited to the UK 100000 Genomes Project, a nationwide multicentre study, was analysed to identify rare pathogenic or likely pathogenic (P/LP) short variants (SNVs and INDELs) and structural variants in 121 CSGs. Results Among 1336 RCC participants (mean 61.3 years [±12SD], range 13–88 years; 64% male), 85 participants (6.4%; 95% CI [5.1, 7.8]) had one or more P/LP germline variant in a wider range of CSGs than previously recognised. A further 64 intragenic variants in CSGs previously associated with RCC were classified as a variant of uncertain significance (VUS) (24 ‘hot VUSs’) and were considered to be of potential clinical relevance as further evaluation might result in their reclassification. Most patients with pathogenic variants in well-established RCC-CSGs were aged < 50 years. Burden test analysis for filtered variants in CSGs demonstrated a significant excess of CHEK2 variants RCC European participants compared to the healthy European controls (P = 0.0019). Conclusions Approximately 6% of patients with RCC unselected for family history have a germline variant requiring additional follow-up analysis. To improve diagnostic yield we suggest expanding the panel of RCC-CSGs tested to include CHEK2 and all SDHx subunits and raising the eligibility criteria for age-based testing.en_UK
dc.identifier.citationYngvadottir B, Andreou A, Bassaganyas L, et al., (2022) Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases. Human Molecular Genetics, Volume 31, Issue 17, 1 September 2022, pp. 3001–3011en_UK
dc.identifier.issn0964-6906
dc.identifier.urihttps://doi.org/10.1093/hmg/ddac089
dc.identifier.urihttp://dspace.lib.cranfield.ac.uk/handle/1826/18008
dc.language.isoenen_UK
dc.publisherOxford Academicen_UK
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.titleFrequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma casesen_UK
dc.typeArticleen_UK

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