期刊
HUMAN MOLECULAR GENETICS
卷 31, 期 17, 页码 3001-3011出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddac089
关键词
-
资金
- European Research Council
- National Institute for Health and Care research (NIHR)
- National Institute for Health and Care research (NIHR) [Cambridge NIHR Biomedical Research Centre] [BRC-1215-20014]
- Cancer Research UK Cambridge Cancer Centre [SSAG/085]
- VHL UK/Ireland
- Cancer Research UK [C1298/A8362, C69256/A30194, A29911]
- Wellcome Trust [214388]
- Medical Research Council
- NIHR Oxford Biomedical Research Centre (Molecular Diagnostics Theme)
- UK Medical Research Council [MR/V033077/1]
- Rosetrees Trust [A2437, A2204]
- Francis Crick Institute from Cancer Research UK [FC10988]
- Francis Crick Institute from UK Medical Research Council [FC10988]
- Francis Crick Institute from Wellcome Trust [FC10988]
- NIHR BRC at the Royal Marsden Hospital
- NIHR BRC at the Institute of Cancer Research [A109]
- Royal Marsden Cancer Charity
- Ventana Medical Systems Inc [10467, 10530]
- National Institute of Health [U01 CA247439]
- Melanoma Research Alliance [686061]
In unselected RCC patients, approximately 6% carry germline variants that require further follow-up analysis. Expanding the genomic panel for RCC susceptibility gene testing can improve diagnostic yield.
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 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据