Inherited renal cell carcinoma(RCC) is associated with multiple familial cancer syndromes but most individuals with features of non-syndromic inherited RCC do not harbour variants in the most commonly tested renal cancer predisposition genes (CPGs). We investigated whether undiagnosed cases might harbour 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 pre-screened 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. This article is protected by copyright. All rights reserved.
Genes, chromosomes & cancer. 2020 Aug 23 [Epub ahead of print]
Philip S Smith, Hannah West, James Whitworth, Bruce Castle, Francis H Sansbury, Anne Y Warren, Emma R Woodward, Marc Tischkowitz, Eamonn R Maher
Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge, UK., Peninsula Clinical Genetics Service, Royal Devon & Exeter NHS Foundation Trust, Royal Devon & Exeter Hospital (Heavitree), Exeter, UK University of Exeter Medical School, University of Exeter, Exeter, UK., All Wales Medical Genomics Service, Cardiff and Vale University Health Board, Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff., Department of Histopathology, Cambridge University NHS Foundation Trust and Cancer Research UK Cambridge Centre, Cambridge, CB2 OQQ, United Kingdom., Manchester Centre for Genomic Medicine and NW Laboratory Genetics Hub, Manchester University Hospitals NHS Foundation Trust, and Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Health Innovation Manchester, Manchester, UK.