DNA 低甲基化模式及其对结直肠癌肿瘤微环境的影响。

IF 4.9 2区 医学 Q2 CELL BIOLOGY Cellular Oncology Pub Date : 2024-08-01 Epub Date: 2024-03-23 DOI:10.1007/s13402-024-00933-x
He Huang, Qian Li, Xusheng Tu, Dongyue Yu, Yundong Zhou, Lifei Ma, Kongyuan Wei, Yuzhen Gao, Guodong Zhao, Ruiqin Han, Fangdie Ye, Chunlian Ke
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引用次数: 0

摘要

背景:最近的研究强调了免疫检查点作为生物标志物在结直肠癌(CRC)治疗中的关键作用,突出了免疫检查点抑制剂的耐药性和反应的动态变化。目前还不完全清楚表观遗传学改变对 CRC 的影响,尤其是与免疫治疗耐药性的关系:我们整合了一个全面的数据集,包括TCGA-COAD、TCGA-READ和多个GEO系列(GSE14333、GSE37892、GSE41258),以及关键的表观遗传数据集(TCGA-COAD、TCGA-READ、GSE77718)。根据欧氏距离和沃德方法对 330 个原发性肿瘤样本进行了分层聚类,以确定不同的群组。免疫微环境使用 MCPcounter 进行评估。除了转录组表达分析外,还采用了机器学习算法来预测DNA甲基化模式及其功能富集。此外还进行了基因组突变分析和治疗反应评估:我们的分析划定了一个具有 CpG 岛(CGI)甲基化的特定肿瘤集群,称为去甲基化表型(DMP)。DMP与氧化磷酸化等代谢途径有关,表明线粒体产生ATP的效率增加,这有助于提高肿瘤的侵袭性。此外,DMP还显示出Myc靶点通路的激活(众所周知,Myc靶点通路可抑制肿瘤免疫)和关键免疫相关通路的下调,这表明肿瘤微环境的特点是免疫力下降和成纤维细胞浸润增加。六种潜在的治疗药物--拉帕替尼、RDEA119、WH.4.023、MG.132、PD.0325901和AZ628--被确定对DMP亚型有效:本研究揭示了一种与免疫检查点抑制剂耐药性相关的新型 CRC 表观遗传表型,提出了表观遗传学分类作为识别 CRC 免疫疗法理想候选者的一种手段,从而向个性化医疗迈出了重要一步。我们的研究结果还突显了针对 DMP 亚型的潜在治疗药物,为量身定制 CRC 治疗策略提供了新途径。
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DNA hypomethylation patterns and their impact on the tumor microenvironment in colorectal cancer.

Background: Recent research underscores the pivotal role of immune checkpoints as biomarkers in colorectal cancer (CRC) therapy, highlighting the dynamics of resistance and response to immune checkpoint inhibitors. The impact of epigenetic alterations in CRC, particularly in relation to immune therapy resistance, is not fully understood.

Methods: We integrated a comprehensive dataset encompassing TCGA-COAD, TCGA-READ, and multiple GEO series (GSE14333, GSE37892, GSE41258), along with key epigenetic datasets (TCGA-COAD, TCGA-READ, GSE77718). Hierarchical clustering, based on Euclidean distance and Ward's method, was applied to 330 primary tumor samples to identify distinct clusters. The immune microenvironment was assessed using MCPcounter. Machine learning algorithms were employed to predict DNA methylation patterns and their functional enrichment, in addition to transcriptome expression analysis. Genomic mutation profiles and treatment response assessments were also conducted.

Results: Our analysis delineated a specific tumor cluster with CpG Island (CGI) methylation, termed the Demethylated Phenotype (DMP). DMP was associated with metabolic pathways such as oxidative phosphorylation, implicating increased ATP production efficiency in mitochondria, which contributes to tumor aggressiveness. Furthermore, DMP showed activation of the Myc target pathway, known for tumor immune suppression, and exhibited downregulation in key immune-related pathways, suggesting a tumor microenvironment characterized by diminished immunity and increased fibroblast infiltration. Six potential therapeutic agents-lapatinib, RDEA119, WH.4.023, MG.132, PD.0325901, and AZ628-were identified as effective for the DMP subtype.

Conclusion: This study unveils a novel epigenetic phenotype in CRC linked to resistance against immune checkpoint inhibitors, presenting a significant step toward personalized medicine by suggesting epigenetic classifications as a means to identify ideal candidates for immunotherapy in CRC. Our findings also highlight potential therapeutic agents for the DMP subtype, offering new avenues for tailored CRC treatment strategies.

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来源期刊
Cellular Oncology
Cellular Oncology ONCOLOGY-CELL BIOLOGY
CiteScore
10.30
自引率
1.50%
发文量
86
审稿时长
12 months
期刊介绍: The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.
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