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

Yngvadottir, Bryndis; Andreou, Avgi; Bassaganyas, Laia; Larionov, Alexey; Cornish, Alex J; Chubb, Daniel; Saunders, Charlie N; ... Maher, Eamonn R; + view all (2022) Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases. Human Molecular Genetics 10.1093/hmg/ddac089. (In press). Green open access

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Abstract

BACKGROUND: 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.

Type: Article
Title: Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/hmg/ddac089
Publisher version: https://doi.org/10.1093/hmg/ddac089
Language: English
Additional information: © The Author(s) 2022. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10147362
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