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分析结直肠癌中异常的DNA甲基化揭示了患者生存时间内基因效应的无形异质性。

Analyzing aberrant DNA methylation in Colorectal cancer uncovered intangible heterogeneity of gene effects in the survival time of patients.

作者信息

Khaniki Saeedeh Hajebi, Shokoohi Farhad, Esmaily Habibollah, Kerachian Mohammad Amin

机构信息

Department of Biostatistics, School of Health, Mashhad University of Medical Sciences, Mashhad, Iran.

Department of Mathematical Sciences, University of Nevada-Las Vegas, Las Vegas, NV 89154, USA.

出版信息

Res Sq. 2023 May 29:rs.3.rs-2957915. doi: 10.21203/rs.3.rs-2957915/v1.

DOI:10.21203/rs.3.rs-2957915/v1
PMID:37397988
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10312929/
Abstract

Colorectal cancer (CRC) involves epigenetic alterations. Irregular gene-methylation alteration causes and advances CRC tumor growth. Detecting differentially methylated genes (DMGs) in CRC and patient survival time paves the way to early cancer detection and prognosis. However, CRC data including survival times are heterogeneous. Almost all studies tend to ignore the heterogeneity of DMG effects on survival. To this end, we utilized a sparse estimation method in the finite mixture of accelerated failure time (AFT) regression models to capture such heterogeneity. We analyzed a dataset of CRC and normal colon tissues and identified 3,406 DMGs. Analysis of overlapped DMGs with several Gene Expression Omnibus datasets led to 917 hypo- and 654 hyper-methylated DMGs. CRC pathways were revealed via gene ontology enrichment. Hub genes were selected based on Protein-Protein-Interaction network including , , , , and , regulating the Wnt signaling pathway. The relationship between identified DMGs/hub genes and patient survival time uncovered a two-component mixture of AFT regression model. The genes , , , , , , and and hub genes , , and were associated with survival time in the most aggressive form of the disease that can serve as potential diagnostic targets for early CRC detection.

摘要

结直肠癌（CRC）涉及表观遗传改变。基因甲基化的异常改变会引发并推动CRC肿瘤的生长。检测CRC中差异甲基化基因（DMG）以及患者生存时间，为癌症的早期检测和预后提供了途径。然而，包括生存时间在内的CRC数据具有异质性。几乎所有研究都倾向于忽略DMG对生存影响的异质性。为此，我们在加速失效时间（AFT）回归模型的有限混合中使用了一种稀疏估计方法来捕捉这种异质性。我们分析了CRC和正常结肠组织的数据集，鉴定出3406个DMG。与几个基因表达综合数据集对重叠DMG的分析，得到了917个低甲基化和654个高甲基化的DMG。通过基因本体富集揭示了CRC通路。基于包括、、、、和在内的蛋白质-蛋白质相互作用网络选择了枢纽基因，这些基因调节Wnt信号通路。已鉴定的DMG/枢纽基因与患者生存时间之间的关系揭示了AFT回归模型的双组分混合。基因、、、、、、和以及枢纽基因、、与该疾病最具侵袭性形式的生存时间相关，可作为早期CRC检测的潜在诊断靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bde6/10312929/72f2bb04916e/nihpp-rs2957915v1-f0010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bde6/10312929/72f2bb04916e/nihpp-rs2957915v1-f0010.jpg

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本文引用的文献

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DNA methylation profile in CpG-depleted regions uncovers a high-risk subtype of early-stage colorectal cancer.CpG 匮乏区域中的 DNA 甲基化图谱揭示了早期结直肠癌的一种高危亚型。
J Natl Cancer Inst. 2023 Jan 10;115(1):52-61. doi: 10.1093/jnci/djac183.
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KIT promotes tumor stroma formation and counteracts tumor-suppressive TGFβ signaling in colorectal cancer.KIT 促进结直肠癌肿瘤基质形成并拮抗肿瘤抑制性 TGFβ 信号通路。
Cell Death Dis. 2022 Jul 16;13(7):617. doi: 10.1038/s41419-022-05078-z.
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Transcriptomic landscape of sodium butyrate-induced growth inhibition of human colorectal cancer organoids.
丁酸钠诱导人结直肠癌细胞类器官生长抑制的转录组学特征。
Mol Omics. 2022 Sep 26;18(8):754-764. doi: 10.1039/d2mo00127f.
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DNA methylation-based diagnostic, prognostic, and predictive biomarkers in colorectal cancer.基于 DNA 甲基化的结直肠癌诊断、预后和预测生物标志物。
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A Prognostic Model Based on Nine DNA Methylation-Driven Genes Predicts Overall Survival for Colorectal Cancer.基于九个DNA甲基化驱动基因的预后模型预测结直肠癌的总生存期。
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Novel Methylation Biomarkers for Colorectal Cancer Prognosis.用于结直肠癌预后的新型甲基化生物标志物
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