Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases.
View/ Open
Date
2022-08-25Author
Yngvadottir, B
Andreou, A
Bassaganyas, L
Larionov, A
Cornish, AJ
Chubb, D
Saunders, CN
Smith, PS
Zhang, H
Cole, Y
Research Consortium, GE
Larkin, J
Browning, L
Turajlic, S
Litchfield, K
Houlston, RS
Maher, ER
Type
Journal Article
Metadata
Show full item recordAbstract
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 and likely pathogenic (P/LP) germline variants in cancer susceptibility genes (CSGs) within a large series of unselected RCC participants. Whole-genome sequencing data on 1336 RCC participants and 5834 controls recruited to the UK 100 000 Genomes Project, a nationwide multicentre study, was analyzed to identify rare P/LP short variants (single nucleotide variants and insertions/deletions ranging from 1 to 50 base pairs) and structural variants in 121 CSGs. Among 1336 RCC participants [mean: 61.3 years (±12 SD), 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 recognized. 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 results in their reclassification. Most patients with P variants in well-established CSGs known to predispose to renal cell carcinoma (RCC-CSGs) were aged <50 years. Burden test analysis for filtered variants in CSGs demonstrated a significant excess of CHEK2 variants in European RCC participants compared with the healthy European controls (P = 0.0019). Approximately, 6% of the 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.
Collections
Subject
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Genetics & Heredity
MEDICAL GENETICS
AMERICAN-COLLEGE
MUTATIONS
CHEK2
PREDISPOSES
ASSOCIATION
GUIDELINE
DIAGNOSIS
GENOMICS
RISK
Research team
Cancer Genomics
Language
eng
Date accepted
2022-04-13
License start date
2022-04-20
Citation
Human Molecular Genetics, 2022, pp. ddac089 -
Publisher
OXFORD UNIV PRESS