应用下一代测序技术检测BRCA1/2及同源重组修复通路多基因胚系突变及相关性分析  

Application of next-generation sequencing in detection of BRCA1/2 and homologous recombination repair pathway multi-genes germline mutation and correlation analysis

作　　者：陈彦丽 卓钟灵 刘畅[2] 谢菲[4] 杨子瑶 刘芃菲 王殊[4] 赵晓涛 Chen Yanli;Zhuo Zhongling;Liu Chang;Xie Fei;Yang Ziyao;Liu Pengfei;Wang Shu;Zhao Xiaotao(Institute of Medical Technology,Peking University Health Science Center,Beijing 100191,China;Department of Laboratory Medicine,Peking University People′s Hospital,Beijing 100044,China;Peking University Fifth School of Clinical Medicine,Beijing 100730,China;Breast Center,Peking University People′s Hospital,Beijing 100044,China;Department of Transfusion,China-Japan Friendship Hospital,Beijing 100029,China)

机构地区：[1]北京大学医学部医学技术研究院,北京100191 [2]北京大学人民医院检验科,北京100044 [3]北京大学第五临床医学院,北京100730 [4]北京大学人民医院乳腺中心,北京100044 [5]中日友好医院输血科,北京100029

出　　处：《中华预防医学杂志》2022年第3期302-311,共10页Chinese Journal of Preventive Medicine

基　　金：北京市自然科学基金(7172225);北京大学人民医院研究与发展基金(RDG2021-03)。

摘　　要：目的应用下一代测序(next-generation sequencing,NGS)技术检测乳腺癌患者及高风险个体胚系基因突变,分析同源重组修复(homologous recombination repair,HR)通路基因突变状态与乳腺癌临床病理特征的相关性,以补充中国乳腺癌相关基因突变数据库。方法本研究为横断面研究,收集2020年10月至2021年9月就诊于北京大学人民医院并自愿接受基因检测的350例乳腺癌患者和49例乳腺癌高风险个体的全血样本。应用NGS检测32个乳腺癌相关基因的胚系突变情况,统计乳腺癌患者发病年龄、肿瘤家族史、单/双侧肿瘤、Luminal分型(Luminal A型、Luminal B型、HER2过表达型和三阴性乳腺癌)、肿瘤大小、肿瘤转移情况等临床病理特征,采用χ^(2)检验和Fisher精确概率检验分析HR通路基因突变与临床病理特征的相关性。结果在350例乳腺癌患者中,64例(18.3%)携带基因致病突变(包括致病和疑似致病两类突变),包括47例(13.4%)BRCA1/2突变,16例(4.6%)非BRCA1/2基因突变,1例(0.3%)BRCA2和FANCL突变。在49例乳腺癌高风险个体中,7例(14.3%)携带基因致病突变,包括6例(12.3%)BRCA1/2突变,1例(2%)ATM突变。BRCA1/2致病突变与乳腺癌发病年龄相关(18%,8.7%,χ^(2)=6.346,P=0.012),发病年龄≤45岁的乳腺癌患者突变频率较高。HR通路基因突变(包括致病、疑似致病和临床意义不明确的三类突变)与单/双侧肿瘤(49.5%,68.4%,χ^(2)=4.841,P=0.028)和Luminal分型(45.7%,62.2%,32%,60%,χ^(2)=12.004,P=0.007)具有相关性,双侧乳腺癌、Luminal B型和三阴性乳腺癌患者突变频率较高。结论乳腺癌高风险个体BRCA1/2致病突变频率与乳腺癌患者相近,对高风险个体进行BRCA1/2检测有利于指导乳腺癌的筛查和预防。早发性乳腺癌、双侧乳腺癌、Luminal B型和三阴性乳腺癌患者HR通路基因突变频率较高,应及早进行HR通路基因检测,为乳腺癌的诊疗预后和风险评估提供实验室依据。Objective To investigate the germline mutation status of related genes in breast cancer patients and high-risk individuals by next-generation sequencing.To analyze the correlations between homologous recombination repair(HR)pathway gene mutation status and clinicopathological characteristics of breast cancer patients.To supplement the database of breast cancer related gene mutations in Chinese population.Methods This study is a cross-sectional study.From October 2020 to September 2021,whole blood samples were collected from 350 breast cancer patients and 49 high-risk individuals,admitted to Peking University People′s Hospital and accepted genetic testing voluntarily.Germline mutations in 32 breast cancer related genes were detected by NGS.The clinicopathological characteristics,including age at the onset,family history,unilateral/bilateral tumor,Luminal typing(Luminal A subtype,Luminal B subtype,HER2-enriched subtype and triple negative breast cancer),tumor size and metastasis,were analyzed,and the correlations between HR pathway gene mutation status and clinicopathological characteristics were analyzed by Chi-squared test and Fisher′s exact probability test.Results Among 350 breast cancer patients,64(18.3%)cases carried gene pathogenic mutations(including pathogenic and likely pathogenic mutations),including 47(13.4%)in BRCA1/2,16(4.6%)in non-BRCA1/2 genes,1(0.3%)in BRCA2 and FANCL.Among 49 high-risk individuals,7(14.3%)cases carried gene pathogenic mutations,including 6(12.3%)in BRCA1/2 and 1(2%)in ATM genes.BRCA1/2 pathogenic mutations were associated with age at the onset(18%,8.7%,χ^(2)=6.346,P=0.012),and the BRCA1/2 pathogenic mutation frequency was higher in patients diagnosed at age≤45 years.HR pathway gene mutations(including pathogenic,likely pathogenic and uncertain significance mutations)were correlated with unilateral/bilateral tumor(49.5%,68.4%,χ^(2)=4.841,P=0.028)and Luminal typing(45.7%,62.2%,32%,60%,χ^(2)=12.004,P=0.007),and the HR mutation frequencies were higher in patients with bilater

关 键 词：乳腺肿瘤 高通量核苷酸序列分析 基因 BRCA1 基因 BRCA2 重组DNA修复 预后 

分 类 号：R737.9[医药卫生—肿瘤]