溴结构域和超末端结构域蛋白家族编码基因胚系罕见变异与中国部分地区人群恶性肿瘤易感性的关系  

Susceptibility study on the germline rare variants of bromodomain and extraterminal domain protein family-encoding genes and patients with cancer living in some regions of China

作　　者：黄烨 李君辉 王欣[3] 邹煜 黄文锋[4] 刘铖 张红星 Huang Ye;Li Junhui;Wang Xin;Zou Yu;Huang Wenfeng;Liu Cheng;Zhang Hongxing(School of Basic Medicine,Anhui Medical University,Hefei 230032,China;State Key Laboratory of Proteomics,Beijing Proteome Research Center,National Center for Protein Sciences,Beijing Institute of Lifeomics,Beijing 102206,China;Department of Stomatology,the Third Medical Centre,Chinese PLA General Hospital,Beijng 100039,China;Department of Oncology,the Second Affiliated Hospital of Guangxi Medical University,Nanning 530007,China;Department of Orthopedics,People′s Hospital of Macheng City,Hubei Province,Macheng 438300,China)

机构地区：[1]安徽医科大学基础医学院,合肥230032 [2]北京生命组学研究所,国家蛋白质科学中心,北京蛋白质组研究中心,蛋白质组学国家重点实验室,北京102206 [3]解放军总医院第三医疗中心口腔科,北京100039 [4]广西医科大学第二附属医院肿瘤内科,南宁530007 [5]湖北省麻城市人民医院骨科,麻城438300

出　　处：《中华医学杂志》2022年第42期3374-3381,共8页National Medical Journal of China

基　　金：国家自然科学基金(81472274)。

摘　　要：目的探讨溴结构域和超末端结构域蛋白(BET)家族编码基因胚系罕见变异与中国部分地区人群恶性肿瘤易感性的关系。方法针对溴结构域蛋白2(BRD2)、BRD3、BRD4基因设计捕获探针,利用Illumina高通量测序平台,对2015年10月至2018年7月解放军总医院、广西医科大学第二附属医院、湖北省麻城市人民医院以及北京吉因加科技有限公司募集的1673例恶性肿瘤患者和1661例非肿瘤对照者的外周血白细胞基因组DNA进行靶向测序。根据基因组分析工具包(GATK)最佳实践指南进行变异检测分析,采用ANNOVAR、VEP软件进行注释,筛选BET家族中胚系罕见变异。为了确定潜在致病性胚系罕见变异,在ClinVar数据库中检索其致病性的临床和实验证据,并采用SIFT和PolyPhen-2软件预测变异的致病性。以Fisher′s精确检验比较病例组和对照组变异率的差异,采用SKAT软件将性别、年龄作为协变量进行多因素回归分析。结果1673例肿瘤患者中,男911例,女762例;年龄(57.9±11.7)岁;肺癌1111例(66.4%),肠癌266例(15.9%),乳腺癌186例(11.1%),食管癌或胃癌110例(6.6%),同期招募非肿瘤对照1661例,其中男821例,女840例;年龄(44.5±13.9)岁。BRD2基因中共有4个潜在致病性胚系罕见变异,且这4个变异仅存在于17例肿瘤患者中。从肿瘤患者和非肿瘤对照中共筛选出5个存在于BRD3基因上的潜在致病性胚系罕见变异,以及8个存在于BRD4基因上的潜在致病性胚系罕见变异。BRD2基因在肿瘤患者中的潜在致病性胚系罕见变异率为1.02%(17/1673),高于非肿瘤对照[0(0/1661);OR=+∞,95%CI:4.81~+∞,P<0.001]。BRD3基因在肿瘤患者中的潜在致病性胚系罕见变异率为0.24%(4/1673),与非肿瘤对照相比,差异无统计学意义[0.12%(2/1661);OR=1.99,95%CI:0.46~10.47,P=0.690]。BRD4基因在肿瘤患者中的潜在致病性胚系罕见变异率为0.18%(3/1673),与非肿瘤对照相比,差异无统计学意义[0.36%(6/1661);OR=0.50,9Objective To explore the relationship between germline rare variants of bromodomain and extraterminal domain(BET)protein family-encoding genes and susceptibility to cancer in some regions of China.Methods Capturing probes were designed for bromodomain-containing protein 2(BRD2),BRD3 and BRD4 genes,and Illumina high-throughput sequencing platform was used to conduct targeted sequencing of genomic DNA of peripheral blood leukocytes from 1673 patients with cancer and 1661 individuals without cancer recruited between October 2015 and July 2018 from Chinese PLA General Hospital,the Second Affiliated Hospital of Guangxi Medical University,People′s Hospital of Macheng City,Hubei Province and Geneplus-Beijing Co.Ltd.Mutation detection and analysis were carried out according to the genome analysis toolkit(GATK)best practice guidelines,ANNOVAR and VEP software were used for annotation,and germline rare variants in BET family were screened.To determine potential pathogenic germline rare variants,clinical and experimental evidence was obtained from the ClinVar database and SIFT and Polyphen-2 softwares were used to predict pathogenicity.Fisher′s exact test was used to compare the difference of the carrying rate of variants in the case group and the control group,and multivariate regression analysis was performed with the SKAT software with sex and age used as covariates.Results Among the 1673 cancer patients,911 were males and 762 were females,with the mean age was(57.9±11.7)years.There were 1,111 cases(66.4%)of lung cancer,266 cases(15.9%)of colorectal cancer,186 cases of breast cancer(11.1%),and 110 cases(6.6%)of esophagus or gastric cancer.In the same period 1,661 non-tumor control individuals were recruited,including 821 males and 840 females,with the mean age was(44.5±13.9)years.It was observed that there were 4 potential pathogenic germline rare variants in BRD2 gene carried by 17 patients with cancer,5 potential pathogenic germline rare variants in BRD3 gene and 8 potential pathogenic germline rare variants in B

关 键 词：肿瘤 溴结构域和超末端结构域 肿瘤易感性 胚系罕见变异 肺癌 肠癌 横断面研究 

分 类 号：R73[医药卫生—肿瘤]