基于二代测序技术探寻一胃癌家系突变情况分析

发布时间：2019-06-20 04:37

【摘要】：目的:胃癌的遗传性机制尚未完全阐明,本研究希望通过应用二代基因测序技术对我们收集到的一个胃癌家系进行肿瘤相关基因筛查,从而明确本家系的致病基因。方法:收集就诊于兰大二院的一个胃癌家系,同一代的子女3人(1人去世)发病,对2名患者进行病史采集、实验室检查、腹部CT检查等,并在获得该家系成员知情同意后,对家系成员完善临床诊断(实验室检查、腹部彩超、胃镜检查、病理检查等),采集该家系成员的外周血于兰大二院肿瘤研究中心存放,待检。总结家系临床-遗传特点,构建家族谱。采用二代基因测序技术对该家系4成员进行遗传肿瘤致病基因检测,检测该家系的基因突变情况。结果:该家系中共有患者3人,1人为高-中分化腺癌,1人为印戒细胞癌,1人病理类型不详,1个家系成员患胃外恶性肿瘤,12个家系成员行胃镜检查,其中9人诊断患胃良性疾病,8个家系成员行Hp检查其中7人诊断患幽门螺杆菌感染。4名家系成员样本经测序分析后,得到平均172×以上的测序深度,所检测总变异数为112864个,共获得了3个可疑致病基因(CDH1、SMAD4、TP53)。但是遗憾的是,由于家系的复杂性,通过对数据进行分析处理,SMAD4基因和TP53基因突变仅存在于部分家系成员,尚不能确定相关基因致病可能。4名家系成员共同存在CDH1基因突变,可是突变位点不保守且测序深度较低,故而可能存在误差,最终未发现该家系明确致病突变。结论:在该胃癌家系中家系成员的临床表现体现出存在较高比例的Hp感染,在该家系第三代成员较早出现萎缩、肠化,而目前防治胃癌最为有效的方法是对胃癌家系成员定期行相关检查。对该家系成员应用基因芯片测序,已排大部分常见遗传性肿瘤致病基因致病可能,证实该家系致病基因可能并非目前已知常见的71种肿瘤相关致病基因,有可能是这71个基因之外的其他胃癌相关基因,也可能是一种目前未被发现的胃癌相关致病基因。通过第二代测序,发现许多新发SNPs和Indels,揭示了第二代测序基因检测技术在胃癌的临床诊断和分子诊断中发挥越来越重要的作用,弥补了传统遗传咨询模式的不足,为有胃癌家族史的患者提供更为有效的帮助,同时为胃癌的早发现、早治疗提供帮助。
[Abstract]:Objective: the genetic mechanism of gastric cancer has not been fully clarified. This study hopes to screen a gastric cancer family with tumor-related genes by using the second generation gene sequencing technique, so as to clarify the pathogenic genes of this family. Methods: three children of the same generation (1 died) were collected from a family of gastric cancer in the second Hospital of Landa University. 2 patients were examined by medical history, laboratory examination and abdominal CT examination, and the clinical diagnosis (laboratory examination, abdominal color Doppler ultrasound, gastroscopy, pathological examination, etc.) was improved after obtaining the informed consent of the family members. The peripheral blood of the family members was collected and stored in the tumor Research Center of Lan sophomore Hospital for examination. The clinical and genetic characteristics of the family were summarized and the family spectrum was constructed. The genetic tumor pathogenic genes of 4 members of the family were detected by the second generation gene sequencing technique, and the gene mutation of the family was detected. Results: there were 3 patients, 1 patient with highly differentiated adenocarcinoma, 1 patient with Indian ring cell carcinoma, 1 patient with unknown pathological type, 1 family member with extragastric malignant tumor, 12 family members were diagnosed with benign gastric diseases, and 7 of 8 family members were diagnosed with HP infection by Hp. The samples of 4 family members were analyzed by sequencing. An average sequencing depth of more than 172 脳 was obtained, the total number of variants was 112864, and three suspected pathogenic genes (CDH1,SMAD4,TP53) were obtained. Unfortunately, due to the complexity of the family, SMAD4 gene and TP53 gene mutations only exist in some family members, and it is not possible to determine the pathogenicity of the related genes. Four family members co-exist CDH1 gene mutations, but the mutation sites are not conservative and the sequencing depth is low, so there may be errors, and finally no clear pathogenic mutations were found in the family. Conclusion: there is a high proportion of Hp infection in the clinical manifestations of the family members of this family, and the third generation members of the family have atrophy and intestinal metathesis. at present, the most effective method for the prevention and treatment of gastric cancer is to carry out regular correlation examination on the family members of gastric cancer. Most of the common genetic tumor pathogenic genes have been sequenced by gene chip sequencing. It is confirmed that the pathogenic genes in this family may not be 71 kinds of tumor related genes known at present, may be other gastric cancer related genes other than these 71 genes, or may be a kind of gastric cancer related pathogenic genes which have not been found at present. Through the second generation sequencing, it is found that many new SNPs and Indels, reveal that the second generation sequencing gene detection technology plays a more and more important role in the clinical diagnosis and molecular diagnosis of gastric cancer, makes up for the deficiency of traditional genetic counseling model, provides more effective help for patients with family history of gastric cancer, and provides help for early detection and early treatment of gastric cancer.
【学位授予单位】：兰州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.2

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