Ali Asif, Jamieson Nigel Balfour, Khan Ishaq N, Chang David, Giovannetti Elisa, Funel Nicola, Frampton Adam E, Morton Jennifer, Sansom Owen, Evans Thomas R Jeffry, Duthie Fraser, McKay Colin J, Samra Jas, Gill Anthony J, Biankin Andrew, Oien Karin A
Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow UK.
Institute of Pathology and Diagnostic Medicine, Khyber Medical University Peshawar, Pakistan.
Am J Cancer Res. 2022 Dec 15;12(12):5668-5683. eCollection 2022.
Despite progress in genomic characterization, no single prognostic marker that can be evaluated using an easy-to-perform and relatively inexpensive method is available for pancreatic ductal adenocarcinoma (PDAC). MicroRNAs, which are stable, tumor- and tissue-specific molecules, are potentially ideal biomarkers, and we established an inter-laboratory validated method to investigate miR-21 as a prognostic biomarker in PDAC. The study samples of PDAC patients were recruited from a test cohort of Glasgow (n = 189) and three validation cohorts of Pisa (n = 69), Sydney (n = 249), and International Cancer Genome Consortium (ICGC) (n = 249). Tissue microarrays were used for miR-21 staining by chromogenic in situ hybridization (CISH). The patients were subdivided into no/low and high miR-21 staining groups using a specific histoscore. Furthermore, miR-21 staining was evaluated against clinicopathological variables and follow-up data by Fisher/log-rank test and Cox proportional models. The prognostic variables found to be significant in univariate analysis ( value < 0.10) were included in multivariate analysis in a backward-stepwise fashion. MiR-21 expression was cytoplasmic, with more consistent staining in the malignant ductal epithelium than in the stroma. The expression of miR-21 was significantly associated with tumor size and lymph node metastasis, whereas no association was observed with other clinicopathological variables. High miR-21 staining (histoscore ≥ 45 [median score]) was an independent predictor of survival in the Glasgow test cohort (HR 2.37, 95% CI: 1.42-3.96, P < 0.0001) and three validation cohorts (Pisa, HR 2.03, 95% CI: 1.21-3.39, P = 0.007; Sydney, HR 2.58, 95% CI (1.21-3.39), P < 0.0001; and ICGC, HR 3.34, 95% CI: 2.07-5.84, P = 0.002) when adjusted for clinical variables in a multivariate model. In comparison to the patients with low miR-21, the patients with high miR-21 expression had significant increase in OS as they benefit from gemcitabine-based adjuvant chemotherapy (Glasgow 16.5 months [with chemotherapy] vs 10.5 months [without chemotherapy]); Sydney 25.0 vs 10.6; ICGC 25.2 vs 11.9. These results indicated that miR-21 is a predictor of survival, prompting prospective trials. Evaluation of miR-21 offers new opportunities for the stratification of patients with PDAC and might facilitate the implementation of clinical management and therapeutic interventions for this devastating disease.
尽管在基因组特征分析方面取得了进展，但目前尚无一种可通过简便易行且相对廉价的方法进行评估的单一预后标志物可用于胰腺导管腺癌（PDAC）。微小RNA是稳定的、肿瘤和组织特异性分子，有可能成为理想的生物标志物，我们建立了一种实验室间验证的方法来研究miR-21作为PDAC的预后生物标志物。PDAC患者的研究样本来自格拉斯哥的一个测试队列（n = 189）以及比萨（n = 69）、悉尼（n = 249）和国际癌症基因组联盟（ICGC）（n = 249）的三个验证队列。组织微阵列用于通过显色原位杂交（CISH）进行miR-21染色。使用特定的组织学评分将患者分为无/低miR-21染色组和高miR-21染色组。此外，通过Fisher/对数秩检验和Cox比例模型针对临床病理变量和随访数据评估miR-21染色。在单变量分析中发现具有显著意义（P值<0.10）的预后变量以向后逐步的方式纳入多变量分析。miR-21表达位于细胞质中，在恶性导管上皮中的染色比在基质中更一致。miR-21的表达与肿瘤大小和淋巴结转移显著相关，而与其他临床病理变量未观察到相关性。高miR-21染色（组织学评分≥45[中位数评分]）是格拉斯哥测试队列（HR 2.37，95%CI：1.42 - 3.96，P < 0.0001）和三个验证队列（比萨，HR 2.03，95%CI：1.21 - 3.39，P = 0.007；悉尼，HR 2.58，95%CI（1.21 - 3.39），P < 0.0001；ICGC，HR 3.34，95%CI：2.07 - 5.84，P = 0.002）在多变量模型中经临床变量校正后的生存独立预测因子。与低miR-21患者相比，高miR-21表达患者的总生存期显著延长，因为他们从基于吉西他滨的辅助化疗中获益（格拉斯哥：16.5个月[化疗]对10.5个月[未化疗]）；悉尼：25.0对10.6；ICGC：25.2对11.9。这些结果表明miR-
