Andersen Morten, Grauslund Morten, Ravn Jesper, Sørensen Jens B, Andersen Claus B, Santoni-Rugiu Eric
Laboratory of Molecular Pathology, Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Laboratory of Molecular Pathology, Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
J Mol Diagn. 2014 Jul;16(4):418-30. doi: 10.1016/j.jmoldx.2014.03.002. Epub 2014 Jun 6.
Malignant pleural mesothelioma (MPM) is difficult to distinguish from reactive mesothelial proliferations (RMPs). It is uncertain whether miRNAs are useful biomarkers for differentiating MPM from RMPs. Thus, we screened with a quantitative RT-PCR (RT-qPCR)-based platform the expression of 742 miRNAs in formalin-fixed, paraffin-embedded, preoperative diagnostic biopsy samples, surgically resected MPM specimens previously treated with chemotherapy, and corresponding non-neoplastic pleura (NNP), from five patients. miR-126, miR-143, miR-145, and miR-652 were significantly down-regulated (≥twofold) in resected MPM and/or chemotherapy-naïve diagnostic tumor biopsy samples. The miRNA expression pattern was validated by RT-qPCR in a cohort of 40 independent MPMs. By performing binary logistic regression on the RT-qPCR data for the four miRNAs, the established four-miRNA classifier differentiated MPM from NNP with high sensitivity and specificity (area under the curve, 0.96; 95% CI, 0.92-1.00). The classifier's optimal logit(P) value of 0.62 separated NNP and MPM samples with a sensitivity of 0.95 (95% CI, 0.89-1.00), a specificity of 0.93 (95% CI, 0.87-0.99), and an overall accuracy of 0.94 (95% CI, 0.88-1.00). The level of miR-126 in MPM was inversely correlated with that of the known target, the large neutral amino acid transporter, small subunit 1 (r = -0.38; 95% CI, -0.63 to -0.06). Overall, these results indicate that these four miRNAs may be suitable biomarkers for distinguishing MPM from RMPs.
恶性胸膜间皮瘤（MPM）很难与反应性间皮增生（RMP）相区分。目前尚不确定miRNA是否是区分MPM与RMP的有用生物标志物。因此，我们使用基于定量逆转录聚合酶链反应（RT-qPCR）的平台，对5例患者的福尔马林固定、石蜡包埋的术前诊断活检样本、先前接受过化疗的手术切除的MPM标本以及相应的非肿瘤性胸膜（NNP）中742种miRNA的表达进行了筛选。在切除的MPM和/或未经化疗的诊断性肿瘤活检样本中，miR-126、miR-143、miR-145和miR-652显著下调（≥两倍）。通过RT-qPCR在40例独立的MPM队列中验证了miRNA表达模式。通过对这四种miRNA的RT-qPCR数据进行二元逻辑回归分析，建立的四miRNA分类器以高灵敏度和特异性区分MPM与NNP（曲线下面积，0.96；95%CI，0.92-1.00）。分类器的最佳logit(P)值为0.62，区分NNP和MPM样本的灵敏度为0.95（95%CI，0.89-1.00），特异性为0.93（95%CI，0.87-0.99），总体准确率为0.94（95%CI，0.88-1.00）。MPM中miR-126的水平与已知靶点大中性氨基酸转运体小亚基1的水平呈负相关（r = -0.38；95%CI，-0.63至-0.06）。总体而言，这些结果表明这四种miRNA可能是区分MPM与RMP的合适生物标志物。
