黄曲霉相关肝癌的基因组特征研究

发布时间：2018-01-01 08:33

本文关键词：黄曲霉相关肝癌的基因组特征研究　出处：《北京协和医学院》2017年博士论文　论文类型：学位论文

【摘要】：背景和目的:饮食中的黄曲霉暴露是肝细胞肝癌的重要危险因素。但是对于黄曲霉相关肝癌的基因组特征我们研究甚少。本研究发现了黄曲霉相关肝癌的基因组特征,同时利用该基因组特征我们可以将黄曲霉相关肝癌从普通人群肝癌中鉴别出来。方法:我们从1990年到2016年,在位于黄曲霉暴露区(38.2%的食物被检测有黄曲霉污染)的启东肝癌防治研究所(启东市人民医院)收集了 49例肝癌病人的肝癌组织和癌旁,并进行了全基因组测序或全外显子组测序。体细胞突变用公认的GATK流程进行进行了生物信息学分析获取,同时用一代测序进行了验证。同时我们还利用非负向量矩阵的算法分析了 TCGA/ICGC的来自中国、美国、法国和日本的1072例普通人群肝癌全外显子组或全基因组数据的突变模式。我们比较了黄曲霉相关肝癌和普通人群肝癌的突变图谱和突变模式的不同,同时鉴别出黄曲霉相关肝癌的基因组特征,这种基因组特征可以较好的将普通人群肝癌中隐匿性的黄曲霉相关肝癌区分出来。我们利用免疫组化方法分析了肿瘤组织的微血管密度、CD34和CD274(PD-L1)的表达水平。结果:黄曲霉相关肝癌频繁的发生CA的突变、GCN的序列偏好以及转录链的偏好。除了 TP53 基因的突变外,我们还发现了 ADGRB1(the adhesion G protein-coupled receptor B1 gene)在黄曲霉相关肝癌的高频突变,并且与黄曲霉相关肝癌组织中的新生血管密度相关。我们发现相比于普通人群肝癌,黄曲霉相关肝癌具有较高的水平的突变相关新生抗原肽、丰富的淋巴细胞浸润和PD-L1阳性的肿瘤细胞。在中国人群的普通肝癌中,我们发现了有9.8%的比例与黄曲霉相关,而在美国、法国、日本的普通人群肝癌有0.4%-3.5%。结论:我们鉴别出黄曲霉相关肝癌中的包括ADGRB1基因在内的特征的性的突变图谱和突变模式。同时这些突变与黄曲霉相关肝癌组织中的新生血管形成和PD-L1表达相关。这些发现有助于我们在普通人群肝癌中去发现这些隐匿性的黄曲霉相关肝癌,并有希望通过anti-PD-1或者anti-PD-L1相关手段进行治疗。
[Abstract]:Background and purpose: dietary aflatoxin exposure is an important risk factor for hepatocellular carcinoma. But the genome characteristics for aflatoxin related liver cancer we studied little. This study showed the genomic characteristics of Aspergillus flavus related liver cancer, at the same time using the genomic features we can put the aflatoxin related liver cancer identified from the general population in hepatocellular carcinoma methods: from 2016 to 1990 in the US, is located in aflatoxin exposed area (38.2% of the food is detection of aflatoxin contamination) study on the prevention and treatment of hepatocellular carcinoma in Qidong (the people's Hospital of Qidong city) collection of hepatocellular carcinoma and carcinoma in 49 cases of liver cancer patients and by whole genome sequencing or whole exome sequencing. Somatic mutations in established GATK process bioinformaticsanalysis acquisition, at the same time with the generation of sequencing was verified. At the same time we also use non negative matrix vector algorithm analysis TCGA/ICGC from Chinese, America, mutation pattern sub group genome data show in France and Japan in 1072 cases of the general population. We compared the hepatocellular carcinoma HCC aflatoxin related HCC and the general population mutation map and mutation patterns and identify genomic characteristics of yellow aspergillus related hepatocellular carcinoma, the genome the better the general population characteristics can be related to hepatocellular carcinoma in Aspergillus flavus hide from. We use immunohistochemical method to analyze tumor microvessel density, CD34 and CD274 (PD-L1). Results: the expression level of aflatoxin related HCC frequent occurrence of CA mutations, GCN sequence preference and preference transcription chain. In addition to mutations in the TP53 gene, we found that the ADGRB1 (the adhesion G protein-coupled receptor B1 gene) high frequency in aflatoxin related hepatocellular carcinoma and mutation, and yellow Microvessel density in hepatocellular carcinoma related Niger. We found that compared to the general population of liver cancer, new mutations associated antigen peptide aflatoxin related hepatocellular carcinoma has a higher level, rich infiltration of lymphocytes and PD-L1 positive tumor cells. In China groups of ordinary liver cancer, we found there are 9.8% associated with the proportion of Aspergillus flavus in the United States, France, Japan, the general population of liver cancer with 0.4%-3.5%. conclusion: We identified including ADGRB1 gene characteristics of Aspergillus flavus related hepatocellular carcinoma of the mutation spectrum and mutation pattern. At the same time, these mutations are associated with angiogenesis in hepatocellular carcinoma aflatoxin formation and PD-L1 expression. These findings help we in the general population of hepatocellular carcinoma to discover these occult aflatoxin related hepatocellular carcinoma, and there is hope for treatment by anti-PD-1 or anti-PD-L1.

【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R735.7

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