Tumor stroma reaction-related gene signature predicts clinical outcome in human hepatocellular carcinoma
Tumor stroma reaction-related gene signature predicts clinical outcome in human hepatocellular carcinoma
复制标题
肿瘤基质反应相关基因特征预测人肝细胞癌的临床结果
DOI：
10.1111/j.1349-7006.2011.01981.x
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发表时间：
2011-08-01
期刊：
影响因子：
5.7
通讯作者：
Fan, Jia
中科院分区：
文献类型：
--
作者：
Gao, Qiang;Wang, Xiao-Ying;Fan, Jia
肿瘤间质是许多潜在的新肿瘤生物标志物的来源，其中免疫应答是非常重要的。关于基质基因表达的变化如何影响肝细胞癌（HCC）的进展知之甚少。我们用定量RT-PCR分析了122例HCC标本中28个基质相关基因的表达，并将结果与患者预后相关。基于28个基因或6-Th 1细胞标志物的表达的层次聚类可以将HCC患者分类为分类学上不同的亚组。通过多变量分析，我们进一步确定了五基因分类器（保护基因IRF 1和GZMB以及风险基因CRTH 2、VEGF和MMP 7）作为复发的重要独立预测因子（风险比[HR]，4.80; 95%置信区间[CI]，2.31-9.96; P = 2.6 x 10（-5））。重要的是，在172个HCC样本的独立组中进一步验证了分类器（HR，2.21; 95%CI，1.20-3.00; P = 0.002）。分类器的预测能力，如通过曲线下面积（原始和验证队列分别为0.713和0.613）测量的，与血管浸润、巴塞罗那临床肝癌分期和TNM分期的预测能力相当。免疫组化染色分析不同肿瘤间质细胞的密度。比较免疫染色和基因表达数据显示基因分类器与两个队列中反应性基质的量显著相关。因此，该特征揭示了免疫应答、血管生成活性和ECM重塑的强预后能力，突出了基质生物学在HCC进展中的重要性。包含在这个新的预测可能是新的治疗干预，或作为独立的预测器使用的目标。（Cancer Sci 2011; 102：1522-1531）
The tumor stroma is a source of many potential new tumor biomarkers, in which the immune response is of major importance. Little is known regarding how changes in stromal gene expression affect hepatocellular carcinoma (HCC) progression. We analyzed the expression of 28 stroma-related genes using quantitative RT-PCR in 122 HCC samples, and related the results to patient prognosis. Hierarchical clustering based on expression of the 28 genes, or the 6-Th1 cell markers, can classify HCC patients into prognostically different subgroups. We further identified a five-gene classifier (protective genes IRF1 and GZMB and risk genes CRTH2, VEGF, and MMP7) as a significant independent prognosticator for recurrence (hazard ratio [HR], 4.80; 95% confidence interval [CI], 2.31-9.96; P = 2.6 x 10(-5)) by multivariate analyses. Importantly, the classifier was further validated in an independent set of 172 HCC samples (HR, 2.21; 95% CI, 1.20-3.00; P = 0.002). The predictive ability of the classifier, as measured by area under the curve (0.713 and 0.613 for original and validation cohorts, respectively), was comparable to those of vascular invasion, Barcelona Clinic Liver Cancer stage, and TNM stage. The densities of various tumor stromal cells were analyzed by immunostaining. Comparing the immunostaining and gene expression data showed significant association of the gene classifier with the amount of reactive stroma in both cohorts. Thus, the signature reveals the strong prognostic capacity of immune responses, angiogenic activity, and ECM remodeling, highlighting the importance of stromal biology in HCC progression. Contained in this novel predictor may be targets suitable for new therapeutic interventions, or for use as independent prognosticators. (Cancer Sci 2011; 102: 1522-1531)