Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases.
Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases.
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DOI：
10.1093/hmg/ddac089
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发表时间：
2022-08-25
影响因子：
3.5
通讯作者：
中科院分区：
文献类型：
--
作者：
肾细胞癌（RCC）发生在许多癌症易感综合征，但对RCC的易感性的遗传结构还没有很好地定义。我们调查了一个大系列的肾癌患者中癌症易感基因（CSG）中致病性和可能致病性（P/LP）生殖系变异的频率。对1336名RCC参与者和5834名对照者的全基因组测序数据进行了分析，以确定121个CSG中罕见的P/LP短变异（单核苷酸变异和1至50个碱基对的插入/缺失）和结构变异。在1336名RCC受试者中[平均年龄：61.3岁（±12 SD），范围：13-88岁; 64%为男性]，85名受试者[6.4%; 95% CI（5.1，7.8）]在比以前认识到的更广泛的CSG中有一个或多个P/LP种系变异。先前与RCC相关的CSG中的另外64个基因内变异被分类为不确定意义的变异（VUS）（24个“热VUS”），并且被认为具有潜在的临床相关性，因为进一步的评估可能导致其重新分类。大多数在已知易患肾细胞癌（RCC-CSG）的成熟CSG中携带P变异的患者年龄<50岁。对CSG中过滤变体的负荷检验分析表明，与健康的欧洲对照相比，欧洲RCC参与者中CHEK 2变体显著过量（P = 0.0019）。大约有6%的RCC家族史患者有生殖系变异，需要额外的随访分析。为了提高诊断率，我们建议扩大RCC-CSG测试的面板，以包括CHEK 2和所有SDHx亚基，并提高基于年龄的测试的资格标准。
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.
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影响因子：
64.8
作者：
Bertolotto, Corine;Lesueur, Fabienne;Bressac-de Paillerets, Brigitte
通讯作者：
Bressac-de Paillerets, Brigitte
影响因子：
14.9
作者：
Howe KL;Achuthan P;Allen J;Allen J;Alvarez-Jarreta J;Amode MR;Armean IM;Azov AG;Bennett R;Bhai J;Billis K;Boddu S;Charkhchi M;Cummins C;Da Rin Fioretto L;Davidson C;Dodiya K;El Houdaigui B;Fatima R;Gall A;Garcia Giron C;Grego T;Guijarro-Clarke C;Haggerty L;Hemrom A;Hourlier T;Izuogu OG;Juettemann T;Kaikala V;Kay M;Lavidas I;Le T;Lemos D;Gonzalez Martinez J;Marugán JC;Maurel T;McMahon AC;Mohanan S;Moore B;Muffato M;Oheh DN;Paraschas D;Parker A;Parton A;Prosovetskaia I;Sakthivel MP;Salam AIA;Schmitt BM;Schuilenburg H;Sheppard D;Steed E;Szpak M;Szuba M;Taylor K;Thormann A;Threadgold G;Walts B;Winterbottom A;Chakiachvili M;Chaubal A;De Silva N;Flint B;Frankish A;Hunt SE;IIsley GR;Langridge N;Loveland JE;Martin FJ;Mudge JM;Morales J;Perry E;Ruffier M;Tate J;Thybert D;Trevanion SJ;Cunningham F;Yates AD;Zerbino DR;Flicek P
通讯作者：
Flicek P
影响因子：
4.6
作者：
Guhan SM;Artomov M;McCormick S;Njauw C-;Stratigos AJ;Shannon K;Ellisen LW;Tsao H
通讯作者：
Tsao H
影响因子：
12.3
作者：
McLaren W;Gil L;Hunt SE;Riat HS;Ritchie GR;Thormann A;Flicek P;Cunningham F
通讯作者：
Cunningham F
影响因子：
4
作者：
Cybulski, C.;Wokolorczyk, D.;Lubinski, J.
通讯作者：
Lubinski, J.