结肠腺瘤性息肉病患者的家系调查及APC预测性基因检测研究  

Pedigree investigation and predictive gene testing of the APC gene for colonic ad⁃enomatous polyposis

作　　者：方瑞华 汪昭明 邱小倩[3] 祝玮晔 葛赛 王成龙 邱耕 高显华 徐晓东 邢俊杰 王颢 张卫 于恩达 赵子夜 Fang Ruihua;Wang Zhaoming;Qiu Xiaoqian;Zhu Weiye;Ge Sai;Wang Chenglong;Qiu Geng;Gao Xianhua;Xu Xiaodong;Xing Junjie;Wang Hao;Zhang Wei;Yu Enda;Zhao Ziye(Department of Colorectal Surgery-Screening and Prevention Center for Hereditary Colorectal Cancer,Changhai Hospital,Naval Medical University,Shanghai 200433,China;Sterile Supply Department,Changhai Hospital,Naval Medical University,Shanghai 200433,China;Dental Clinic,Changhai Hospital,Naval Medical University,Shanghai 200433,China;Department of Ophthalmology,Changhai Hospital,Naval Medical University,Shanghai 200433,China;Department of Digestive Diseases,Beijing Cancer Hospital-Department of Digestive Oncology,Beijing Institute for Cancer Re-search,Beijing 100142,China;Department of Digestive Diseases,The 73rd Group Military Hospital of the People’s Liberation Army,Xiamen 361003,Fujian,China;Shanghai Jianyan Biotechnology Co.,Ltd,Shanghai 201400,China)

机构地区：[1]上海长海医院肛肠外科/遗传性结直肠癌筛查防治中心,上海200433 [2]上海长海医院消毒供应科,上海200433 [3]上海长海医院口腔科,上海200433 [4]上海长海医院眼科,上海200433 [5]北京肿瘤医院消化内科暨北京市肿瘤防治研究所消化肿瘤内科,北京100142 [6]解放军第73集团军医院消化内科,福建厦门361003 [7]上海鉴研生物技术有限公司,上海201400

出　　处：《结直肠肛门外科》2023年第5期461-468,共8页Journal of Colorectal & Anal Surgery

基　　金：国家自然科学基金(81870455);上海长海医院“234学科攀峰计划”(2019YXK036,2020YXK022)。

摘　　要：目的对于结肠腺瘤性息肉病患者的家系调查和预测性基因检测在我国尚未系统开展,其实践价值也未见报道。本研究意在探索预测性基因检测对我国结肠腺瘤性息肉病家系的实际意义。方法我们基于上海长海医院遗传性结直肠癌筛查防治中心开展了一项横断面调查,即在家系调查的基础上开展APC相关息肉病家系的预测性基因检测。先证者临床信息的收集和家系调查将围绕结肠息肉病的临床分型等核心信息开展,并锁定先证者可追踪的一级亲属作为预测性基因检测对象。APC基因检测方法包括Sanger测序、二代测序和多重连锁探针扩增分析,所获得APC基因变异包括点突变和大片段缺失。基于按照年龄分层得出的变异检出率探讨开展预测性基因检测的恰当时机。结果研究共纳入APC相关息肉病家系65个,先证者临床表现包含结肠腺瘤、胃及十二指肠腺瘤、甲状腺肿瘤、先天性视网膜色素上皮肥大、颌骨及牙齿异常、硬纤维瘤等。预测性基因检测对象为130名无症状亲属,其中男性61名。65个家系共携带49种APC基因胚系变异,其中13种变异既往未见报道。亲属受检者中位年龄为12(6,24)岁,检测发现家系变异携带者共52名,变异检出率为40%。限定受检者年龄上限进行分析,以50岁为整体的年龄上限,每5岁作为一档,变异检出率分别为53.8%、48.2%、52.1%、50.6%、47.6%、44.2%、43.0%、41.6%、40.9%、40.3%。7岁、14岁、18岁这三个重要年龄节点的变异检出率分别为52.6%、52.1%、48.8%。将受检者限定为先证者的晚辈,则变异检出率为44.1%(52/118)。结论对以APC相关息肉病为代表的致病变异明确的结肠腺瘤性息肉病家系来说,预测性基因检测能够实现致病变异携带者的早期确认从而实现早诊早治。预测性基因检测的变异检出率整体上呈现出随受检者年龄降低而增加的趋势,受检者年龄在25岁及以�Objectives Pedigree investigation and predictive genetic testing for colonic adenomatous polyposis(CAP)has not systematically conducted in China,and its practical value remains unreported.This study aims to explore the practical significance of predictive genetic testing for families affected by CAP in China.Methods A cross-sectional study,conducted by the Screening and Prevention Center for Hereditary Colorectal Cancer at Changhai Hospital,aimed to perform predictive genetic testing for families affected by APC-associated polyposis(AAP)through pedigree investigation.Clinical information and pedigree investigation of the probands focused on core details such as the clinical classification of colon polyposis.Subjects for predictive genetic testing included first-degree relatives who could be traced.The testing methods for APC gene encompassed Sanger sequencing,second-generation sequencing,and multiplex ligation-dependent probe amplification.Detected APC gene mutations comprised oligonucleotide variations and large fragment deletions.The optimal timing for conducting predictive genetic testing was explored considering the detection rate of gene mutations stratified by age.Results The study included a total of 65 families affected by AAP.The probands exhibited diverse clinical manifestations,including colon adenoma,gastric and duodenal adenoma,thyroid cancer,congenital hypertrophy of the retinal pigment epithelium,abnormalities of jaw and tooth,and hard fibroma.Predictive genetic testing was conducted on 130 asymptomatic relatives(61 males).Among the 65 families,a total of 49 germline mutations in the APC gene were detected,including 13 mutations that had not been previously reported.The median age of the subjects was 12(range:6 to 24 years old),with 52 mutation carriers detected among family members,resulting in a mutation detection rate of 40%.When restricting the age of the subjects to the overall age limit of 50 years(in 5-year-increments),the mutation detection rates were 53.8%,48.2%,52.1%,50.6%,47.6%,44.2%,43.

关 键 词：结肠腺瘤性息肉病 家族性腺瘤性息肉病 APC基因 预测性基因检测 

分 类 号：R656.9[医药卫生—外科学]