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Identification of a robust functional subpathway signature for pancreatic ductal adenocarcinoma by comprehensive and integrated analyses.
Cell Communication and Signaling ( IF 8.4 ) Pub Date : 2020-03-02 , DOI: 10.1186/s12964-020-0522-4
Ping Wang 1, 2 , Chunlong Zhang 3 , Weidong Li 1, 4 , Bo Zhai 1, 4 , Xian Jiang 1 , Shiva Reddy 5 , Hongchi Jiang 1 , Xueying Sun 1
Affiliation  

BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy and its mortality continues to rise globally. Because of its high heterogeneity and complex molecular landscapes, published gene signatures have demonstrated low specificity and robustness. Functional signatures containing a group of genes involved in similar biological functions may display a more robust performance. METHODS The present study was designed to excavate potential functional signatures for PDAC by analyzing maximal number of datasets extracted from available databases with a recently developed method of FAIME (Functional Analysis of Individual Microarray Expression) in a comprehensive and integrated way. RESULTS Eleven PDAC datasets were extracted from GEO, ICGC and TCGA databases. By systemically analyzing these datasets, we identified a robust functional signature of subpathway (path:00982_1), which belongs to the drug metabolism-cytochrome P450 pathway. The signature has displayed a more powerful and robust capacity in predicting prognosis, drug response and chemotherapeutic efficacy for PDAC, particularly for the classical subtype, in comparison with published gene signatures and clinically used TNM staging system. This signature was verified by meta-analyses and validated in available cell line and clinical datasets with chemotherapeutic efficacy. CONCLUSION The present study has identified a novel functional PDAC signature, which has the potential to improve the current systems for predicting the prognosis and monitoring drug response, and to serve a linkage to therapeutic options for combating PDAC. However, the involvement of path:00982_1 subpathway in the metabolism of anti-PDAC chemotherapeutic drugs, particularly its biological interpretation, requires a further investigation. Video Abstract.

中文翻译:

通过全面和综合的分析,为胰腺导管腺癌的鲁棒功能子途径签名的鉴定。

背景技术胰腺导管腺癌(PDAC)是一种高度致死性的恶性肿瘤,其死亡率在全球范围内持续上升。由于其高度的异质性和复杂的分子格局,已发表的基因签名显示出较低的特异性和鲁棒性。包含一组涉及相似生物学功能的基因的功能签名可能会显示出更强大的性能。方法本研究旨在通过使用综合开发的FAIME(单个微阵列表达的功能分析)方法分析从可用数据库中提取的最大数据集,挖掘PDAC的潜在功能特征。结果从GEO,ICGC和TCGA数据库中提取了11个PDAC数据集。通过系统地分析这些数据集,我们鉴定了一个强大的子通路功能签名(通路:00982_1),该通路属于药物代谢-细胞色素P450通路。与已发表的基因签名和临床使用的TNM分期系统相比,该签名在预测PDAC(尤其是经典亚型)的预后,药物反应和化学治疗功效方面显示出更强大的功能。该特征通过荟萃分析进行验证,并在具有化学治疗功效的可用细胞系和临床数据集中进行了验证。结论本研究确定了一种新颖的功能性PDAC签名,它具有改善现有的预测预后和监测药物反应的系统的潜力,并可以与抗PDAC的治疗选择联系起来。但是,涉及的路径:抗PDAC化疗药物代谢中的00982_1子途径,尤其是其生物学解释,需要进一步研究。录像摘要。
更新日期:2020-04-22
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