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

遗传 ›› 2025, Vol. 47 ›› Issue (5): 558-572.doi: 10.16288/j.yczz.24-291

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:2025-05-20 发布日期:2025-02-10
通讯作者: 贾学渊，博士，副教授，研究方向：遗传病与肿瘤的发病机制。E-mail: jiaxueyuan@hrbmu.edu.cn
作者简介:安梦婷，硕士研究生，专业方向：医学遗传学。E-mail: anmenting814@163.com；
郭冠麟，硕士研究生，专业方向：医学遗传学。E-mail: ggl950913@163.com。
第一联系人：
安梦婷和郭冠麟并列第一作者。
基金资助:
黑龙江省自然科学杰出青年基金项目(JQ2022C004);黑龙江省自然科学基金联合引导项目(LH2021H006);哈尔滨医科大学少帅揭榜项目(HMUMIF-21007)

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
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:2025-05-20 Online:2025-02-10
Supported by:
Natural Science Foundation of Heilongjiang Province of China(JQ2022C004);Joint Guiding Project of Heilongjiang Natural Science Foundation(LH2021H006);HMU Marshal Initiative Funding(HMUMIF-21007)

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 minutes，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≥50 kb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 minutes (DMs) are extrachromosomal circular chromosomes that carry amplified oncogenes or drug resistance genes, and they 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, we utilize bioinformatics methods to analyze genomic copy number variation data from the CCLE cell line database and TCGA solid tumor database. We analyze and summarize the genomic features of tumor samples with double minutes. Based on these features, we classify gastric cancer samples. We use the FANTOM5 database, R package “GenomicRanges”, Bedtools, and MEME SUITE to analyze the functions of the enhancers on double minutes and their regulated target genes in gastric cancer. Next, we apply the CIBERSORT package and the GDSC drug database to analyze immune cell infiltration and drug resistance in gastric cancer samples with and without double minutes from TCGA. The results show that the genome with a copy number greater than 10 and genomic fragments longer than 50 kb play a significant role. The regulatory role of double minutes enhancers affects drug resistance and tumor immunity, with disruptions in the enhancer-transcription factor-target gene regulatory loops also linked to tumor immunity. Furthermore, the target genes regulated by double minutes enhancers not only alter the expression of immune-related genes but also contribute to 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, 2025, 47(5): 558-572.

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), 2025, 47(5): 558-572.

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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

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