dc.contributor.author | Yngvadottir, B | |
dc.contributor.author | Andreou, A | |
dc.contributor.author | Bassaganyas, L | |
dc.contributor.author | Larionov, A | |
dc.contributor.author | Cornish, AJ | |
dc.contributor.author | Chubb, D | |
dc.contributor.author | Saunders, CN | |
dc.contributor.author | Smith, PS | |
dc.contributor.author | Zhang, H | |
dc.contributor.author | Cole, Y | |
dc.contributor.author | Research Consortium, GE | |
dc.contributor.author | Larkin, J | |
dc.contributor.author | Browning, L | |
dc.contributor.author | Turajlic, S | |
dc.contributor.author | Litchfield, K | |
dc.contributor.author | Houlston, RS | |
dc.contributor.author | Maher, ER | |
dc.coverage.spatial | England | |
dc.date.accessioned | 2022-06-24T09:18:17Z | |
dc.date.available | 2022-06-24T09:18:17Z | |
dc.date.issued | 2022-08-25 | |
dc.identifier | 6569867 | |
dc.identifier.citation | Human Molecular Genetics, 2022, pp. ddac089 - | |
dc.identifier.issn | 0964-6906 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5188 | |
dc.identifier.eissn | 1460-2083 | |
dc.identifier.eissn | 1460-2083 | |
dc.identifier.doi | 10.1093/hmg/ddac089 | |
dc.description.abstract | 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. | |
dc.format | Print-Electronic | |
dc.format.extent | ddac089 - | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | OXFORD UNIV PRESS | |
dc.relation.ispartof | Human Molecular Genetics | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Science & Technology | |
dc.subject | Life Sciences & Biomedicine | |
dc.subject | Biochemistry & Molecular Biology | |
dc.subject | Genetics & Heredity | |
dc.subject | MEDICAL GENETICS | |
dc.subject | AMERICAN-COLLEGE | |
dc.subject | MUTATIONS | |
dc.subject | CHEK2 | |
dc.subject | PREDISPOSES | |
dc.subject | ASSOCIATION | |
dc.subject | GUIDELINE | |
dc.subject | DIAGNOSIS | |
dc.subject | GENOMICS | |
dc.subject | RISK | |
dc.title | Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2022-04-13 | |
dc.date.updated | 2022-06-24T09:16:15Z | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1093/hmg/ddac089 | |
rioxxterms.licenseref.startdate | 2022-04-20 | |
rioxxterms.type | Journal Article/Review | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/35441217 | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Cancer Genomics | |
pubs.publication-status | Published online | |
icr.researchteam | Cancer Genomics | |
dc.contributor.icrauthor | Cornish, Alexander | |
dc.contributor.icrauthor | Saunders, Charles | |
dc.contributor.icrauthor | Houlston, Richard | |