Pathogenic germline variants in patients with features of hereditary renal cell carcinoma: Evidence for further locus heterogeneity.


Type
Article
Change log
Authors
West, Hannah 
Castle, Bruce 
Sansbury, Francis H  ORCID logo  https://orcid.org/0000-0002-5048-3309
Abstract

Inherited 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.

Description
Keywords
inherited, predisposition, renal cell carcinoma, Adolescent, Adult, Aged, BRCA1 Protein, Carcinoma, Renal Cell, Checkpoint Kinase 2, Child, Fanconi Anemia Complementation Group Proteins, Female, Genetic Heterogeneity, Genetic Testing, Germ-Line Mutation, Humans, Kidney Neoplasms, Male, Microphthalmia-Associated Transcription Factor, Middle Aged, RNA Helicases
Journal Title
Genes Chromosomes Cancer
Conference Name
Journal ISSN
1045-2257
1098-2264
Volume Title
60
Publisher
Wiley
Rights
All rights reserved
Sponsorship
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC 2012-2017)
Cancer Research UK (C20/A20917)