基于生物信息学分析胃癌双微体中增强子的调控机制

doi:10.16288/j.yczz.24-291

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基于生物信息学分析胃癌双微体中增强子的调控机制

安梦婷^1,2，郭冠麟^1,2，吴杰^1,2，孙文靖^1,2，贾学渊^1,2

1. 哈尔滨医科大学基础医学院医学遗传学教研室，哈尔滨 150081
2. 中国遗传资源保护与疾病防控教育部重点实验室（哈尔滨医科大学），哈尔滨 150081

收稿日期:2024-12-17 修回日期:2025-02-04 出版日期:2025-02-10 发布日期:2025-02-10
基金资助:
黑龙江省自然科学杰出青年基金项目;黑龙江省自然科学基金联合引导项目;哈尔滨医科大学少帅揭榜项目

Analysis of Regulatory Mechanisms of Enhancers in Gastric Cancer with Double Minute Chromosomes based on Bioinformatics

Mengting An^1,2, Guanlin Guo^1,2, Jie Wu^1,2, Wenjing Sun^1,2, Xueyuan Jia^1,2

1. Department of Medical Genetics, School of Bastic Medical Sciences, Harbin Medical University, Harbin 150081, China

2. Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin 150081, China

Received:2024-12-17 Revised:2025-02-04 Published:2025-02-10 Online:2025-02-10

摘要/Abstract

摘要： 胃癌（gastric cancer，GC）在全球范围内的发病率和死亡率均居高位。双微体（double minute chromosomes，DMs）是一种染色体外的环状染色体，常携带有癌基因或耐药基因，其与肿瘤发生及耐药性密切相关。为深入探索双微体在胃癌发展中的作用及调控机制，本研究利用生物信息学方法通过分析CCLE细胞系数据库和TCGA实体瘤数据库中的基因组拷贝数变异数据，总结含双微体肿瘤样本的基因组特征，依此特征对胃癌样本进行分类。接着使用FANTOM5数据库、R 包“GenomicRanges”、Bedtools工具以及MEME SUITE分析胃癌双微体上增强子及其调控的靶基因的功能。然后利用CIBERSORT包和GDSC药物数据库对TCGA中的含和不含的胃癌样本进行免疫细胞浸润分析和耐药分析。研究显示，胃癌中的双微体基因组特征包括一类拷贝数超过10且长度不少于50kb的基因组片段。双微体增强子的调控作用影响了耐药性和肿瘤免疫，其中增强子-转录因子-靶基因的调控回路扰动也与肿瘤免疫相关。进一步分析发现，双微体增强子调控的靶基因不仅导致了免疫相关基因表达的改变，还使得胃癌样本对常见化疗药物展现出更强的不敏感性，并且耐药相关靶基因在含双微体的胃癌样本中高表达并与不良预后密切相关。综上所述，该项研究为含有双微体的胃癌个体治疗提供了新的见解。

关键词: 双微体, 增强子, 胃癌, 肿瘤免疫, 肿瘤耐药性, 生物信息学

Abstract: Gastric cancer (GC) has a high incidence and mortality rate globally. Double minute chromosomes (DMs) are extrachromosomal circular chromosomes, that carry amplified oncogenes or drug resistance genes, and are closely associated with tumorigenesis and drug resistance. To investigate the role and regulatory mechanisms of double minutes in the malignant progression of gastric cancer, this study utilized bioinformatics methods to analyze genomic copy number variation data in the CCLE cell line database and TCGA solid tumor database, the genomic features of the tumor samples with double minutes were analyzed and summarized. Based on these features, gastric cancer samples were classified. FANTOM5 database, R package "GenomicRanges", Bedtools and MEME SUITE were used to analyze the functions of the enhancers on double minutes and their regulated target genes in gastric cancer. Then, the CIBERSORT package and the GDSC drug database were used to analyze immune cell infiltration and drug resistance in gastric cancer samples with and without double minutes from TCGA. The results showed that the genome with the copy number greater than 10 and the genomic fragments with a length of 50kb or more. The regulatory role of double minutes enhancers affects drug resistance and tumor immunity, with perturbations in the enhancer-transcription factor-target gene regulatory loops also associated with tumor immunity. Furthermore, the target genes regulated by double minutes enhancers not only lead to changes in the expression of immune-related genes but also result in increased drug resistance to common chemotherapy agents in gastric cancer samples. High expression of drug resistance-related target genes in gastric cancer samples with double minutes is closely associated with poor prognosis. This study provides new insights for the treatment of gastric cancer patients with double minutes.

Key words: double minute chromosomes, enhancer, gastric cancer, tumor immunity, tumor drug resistance, bioinformatics

安梦婷, 郭冠麟, 吴杰, 孙文靖, 贾学渊. 基于生物信息学分析胃癌双微体中增强子的调控机制[J]. 遗传, doi: 10.16288/j.yczz.24-291.

Mengting An, Guanlin Guo, Jie Wu, Wenjing Sun, Xueyuan Jia. Analysis of Regulatory Mechanisms of Enhancers in Gastric Cancer with Double Minute Chromosomes based on Bioinformatics[J]. Hereditas(Beijing), doi: 10.16288/j.yczz.24-291.

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基于生物信息学分析胃癌双微体中增强子的调控机制

Analysis of Regulatory Mechanisms of Enhancers in Gastric Cancer with Double Minute Chromosomes based on Bioinformatics

Mengting An^1,2, Guanlin Guo^1,2, Jie Wu^1,2, Wenjing Sun^1,2, Xueyuan Jia^1,2

1. Department of Medical Genetics, School of Bastic Medical Sciences, Harbin Medical University, Harbin 150081, China

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基于生物信息学分析胃癌双微体中增强子的调控机制

Analysis of Regulatory Mechanisms of Enhancers in Gastric Cancer with Double Minute Chromosomes based on Bioinformatics

Mengting An1,2, Guanlin Guo1,2, Jie Wu1,2, Wenjing Sun1,2, Xueyuan Jia1,2

1. Department of Medical Genetics, School of Bastic Medical Sciences, Harbin Medical University, Harbin 150081, China

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Mengting An^1,2, Guanlin Guo^1,2, Jie Wu^1,2, Wenjing Sun^1,2, Xueyuan Jia^1,2