癌症易感基因中的罕见种系变异与肺癌风险的关联
Association Between Rare Germline Variants in Cancer Susceptibility Genes and Lung Cancer Risk.
作者
作者单位
- Department of Cardiovascular and Thoracic Surgery, Rush University Medical Center, Chicago, Illinois, USA.
- Program for Genomic Translational Research, Endeavor Health, Evanston, IL.
- Department of Medicine, Endeavor Health, Evanston, IL; Pritzker School of Medicine, University of Chicago, Chicago, IL.
- Program for Genomic Translational Research, Endeavor Health, Evanston, IL; Pritzker School of Medicine, University of Chicago, Chicago, IL.
- Department of Surgery, Endeavor Health, Evanston, IL; Pritzker School of Medicine, University of Chicago, Chicago, IL. Electronic address: seth.krantz@endeavorhealth.org.
摘要
中文
已确立的肺癌种系易感基因较少。本研究旨在评估已知遗传性癌症基因中的种系变异与肺癌风险的关联。我们分析了两组欧洲血统受试者的数据：来自 UK Biobank 的 2272 例肺癌病例和 185510 例对照，以及来自 Rush University Medical Center（RUSH）的 824 例肺癌病例和来自基因组聚合数据库（gnomAD）的 56878 例人群对照。首先采用基于基因的负荷检验（robust SKAT-O）在 UK Biobank 中检测 123 个 ClinGen 策展的遗传性癌症基因中罕见致病性种系变异与肺癌风险的关系。在 UK Biobank 中，10 个基因的罕见种系变异与肺癌呈名义显著关联（p<0.05），TP53 呈临界信号（p=0.11）。这些基因在 RUSH/gnomAD 数据集中进一步验证，荟萃分析确定了支持 8 个基因与肺癌风险增加相关的提示性证据（p<0.05），包括 3 个既往报道的肺癌基因（ATM、BRCA2、TP53）和 5 个新基因（RB1、MET、CYLD、PDGFRA、CTNNA1）。在 UK Biobank 新发肺癌队列中，这 8 个基因中聚集的罕见致病性变异与肺癌风险增加及更早的诊断年龄显著相关，且独立并补充于招募时吸烟史之外。基于两个大型独立数据集，本研究获得了支持 8 个遗传性癌症基因中罕见种系变异与肺癌相关的提示性证据。
English
Few germline susceptibility genes have been well established for lung cancer. We aimed to evaluate associations between germline variants in known hereditary cancer genes and lung cancer risk. We analyzed subjects of European ancestry from two datasets: 2,272 LC cases and 185,510 controls from the UK Biobank, and 824 LC cases from Rush University Medical Center (RUSH) with 56,878 population controls from the Genome Aggregation Database (gnomAD). Rare pathogenic germline variants in 123 ClinGen-curated hereditary cancer genes were first tested for lung cancer risk in the UK Biobank using gene-based burden testing (robust SKAT-O). Genes with suggestive associations were further evaluated in the RUSH/gnomAD dataset. Meta-analysis of the two datasets was performed to estimate overall evidence and pooled odds ratios. Rare germline variants in ten genes showed nominally significant associations with lung cancer in the UK Biobank (p<0.05), and TP53 showed a borderline signal (p=0.11). These genes were tested in the RUSH/gnomAD dataset, and meta-analysis identified suggestive evidence supporting eight genes associated with increased lung cancer risk (p<0.05), including three previously reported lung cancer genes (ATM, BRCA2, TP53) and five novel genes (RB1, MET, CYLD, PDGFRA, CTNNA1). In the UK Biobank incident lung cancer cohort, aggregated rare pathogenic variants in these eight genes were significantly associated with lung cancer risk and earlier age at lung cancer diagnosis, independent and complementary to smoking history at recruitment. Suggestive evidence supporting associations between rare germline variants in eight hereditary cancer genes and lung cancer were obtained from two large independent datasets.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 5.3