Identification of diagnostic markers of pancreatic ductal adenocarcinoma using transcriptomic tumour and blood sample data

Clinical and translational discovery Pub Date : 2023-10-18 DOI:10.1002/ctd2.248

Aristeidis Sionakidis, Panagiotis Nikolaos Lalagkas, Andigoni Malousi, Ioannis S. Vizirianakis

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Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is the most frequently diagnosed form of pancreatic cancer worldwide. PDAC is associated with a poor survival rate mainly due to the disease being usually diagnosed at late stages.

Methods

Publicly available gene expression data from 10 studies with tumour tissue (448 samples) and/or blood samples (128 samples) from PDAC patients were pooled together and analyzed for the identification of stage-specific and global diagnostic markers using differential gene expression analysis. The list of statistically significant ( $p_{a d j} < 0.05$ ) differentially expressed genes were used to carry out enrichment analysis via active subnetworks and miRNA enrichment analysis. We then used the results from these analyses to identify the most significant genes and pathways and map these to marketed drugs’ pharmacological targets. The same process was replicated for studies with blood samples and results were compared to those from the tissue analysis. A set of consistently deregulated genes (pancreatic tumour signature, PTS) in both tissue and blood samples was derived and validated in external cohorts and The Cancer Genome Atlas (TCGA) data.

Results

Notable gene expression deregulation was found in all tumour stages with significant overlap. We identified 820 consistently deregulated genes (PTS) in tissue samples of all stages and blood samples. Active subnetwork analysis revealed enriched ribosome, proteasome, adherens junction and cell cycle pathways across all stages and blood samples. Our findings suggest that microRNA (miRNA) contribution to PDAC pathology plays a significant role and is probably mediated by distinct miRNAs across stages of PDAC. Stage-specific enriched miRNAs with diagnostic potential included miR-21, miR-29, miR-124 and miR-30, for stages 1–4, respectively. By investigating the pharmacogenetic interactions of the identified targets with clinically approved drugs, we outline potential paths for personalized interventions. Importantly, the PTS showed a significant association with survival in TCGA data.

Conclusion

Thus, we present a compilation of protein-coding markers and miRNAs that hold potential as a diagnostic tool for the early detection of PDAC, as well as for designing novel therapeutic strategies aimed at improving patient outcomes.

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利用转录组肿瘤和血样数据鉴定胰腺导管腺癌的诊断标志物

背景胰腺导管腺癌（PDAC）是世界范围内诊断最常见的胰腺癌症。PDAC与低生存率相关，主要是由于该疾病通常在晚期诊断。方法将10项针对PDAC患者肿瘤组织（448份样本）和/或血液样本（128份样本）的公开可用基因表达数据汇集在一起，并使用差异基因表达分析进行分析，以鉴定分期特异性和全局诊断标志物。具有统计学意义的列表（p a d j<；0.05$｛p_｛adj｝｝\<；\；0.05$）差异表达基因用于通过活性子网络和miRNA富集分析进行富集分析。然后，我们使用这些分析的结果来确定最重要的基因和途径，并将其映射到上市药物的药理学靶点。同样的过程也被用于血液样本的研究，并将结果与组织分析结果进行比较。在外部队列和癌症基因组图谱（TCGA）数据中，导出并验证了组织和血液样本中一组一致失调的基因（胰腺肿瘤特征，PTS）。结果在所有肿瘤分期中均发现明显的基因表达失调，并有明显的重叠。我们在所有阶段的组织样本和血液样本中鉴定了820个一致失调的基因（PTS）。主动子网络分析揭示了所有阶段和血液样本中富集的核糖体、蛋白酶体、粘附分子连接和细胞周期途径。我们的研究结果表明，微小RNA（miRNA）对PDAC病理的贡献起着重要作用，并且可能是由PDAC各个阶段的不同miRNA介导的。具有诊断潜力的阶段特异性富集的miRNA分别包括1-4阶段的miR-21、miR-29、miR-124和miR-30。通过研究已确定的靶点与临床批准药物的药物遗传学相互作用，我们概述了个性化干预的潜在途径。重要的是，PTS在TCGA数据中显示出与生存率显著相关。结论因此，我们提供了一份蛋白质编码标记物和miRNA的汇编，它们有可能成为PDAC早期检测的诊断工具，以及设计旨在改善患者预后的新治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and translational discovery

CiteScore

1.00

自引率

0.00%

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