Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival
Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival
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DOI：
10.1073/pnas.0905139106
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发表时间：
2009-12-01
影响因子：
11.1
通讯作者：
Bhardwaj, Nina
中科院分区：
文献类型：
--
作者：
Bogunovic, Dusan;O'Neill, David W.;Bhardwaj, Nina
虽然转移性黑色素瘤的缓解率通常很低，但一些患者可以在转移后长期存活。我们使用基因表达谱、有丝分裂指数(MI)以及肿瘤浸润性白细胞(TIL)和CD3+细胞在转移灶中的定量来寻找这一观察的分子基础，并开发改进的方法来预测患者的生存。我们确定了一组与复发后生存相关的266个基因。与生存呈正相关的基因主要与免疫反应相关(如ICOS、CD3d、ZAP70、TRAT1、TARP、GZMK、LCK、CD2、CXCL13、CCL19、CCR7、VCAM1)，而与生存呈负相关的基因(如PDE4D、CDK2、GREF1、NUSAP1、SPC24)与细胞增殖有关。此外，这4个参数中的任何一个(预先验证的基因表达特征、TIL、CD3，尤其是MI)都提高了肿瘤、淋巴结、转移分期预测复发后生存率的能力；MI是最显著的贡献因素(HR=2.13，P=0.0008)。免疫反应基因的表达特征以及TIL和CD3+细胞的存在表明免疫监测是延长这些患者生存的一种机制，并表明患者亚型的改善超出了当前的TNM分期。
Although remission rates for metastatic melanoma are generally very poor, some patients can survive for prolonged periods following metastasis. We used gene expression profiling, mitotic index (MI), and quantification of tumor infiltrating leukocytes (TILs) and CD3+ cells in metastatic lesions to search for a molecular basis for this observation and to develop improved methods for predicting patient survival. We identified a group of 266 genes associated with postrecurrence survival. Genes positively associated with survival were predominantly immune response related (e. g., ICOS, CD3d, ZAP70, TRAT1, TARP, GZMK, LCK, CD2, CXCL13, CCL19, CCR7, VCAM1) while genes negatively associated with survival were cell proliferation related (e. g., PDE4D, CDK2, GREF1, NUSAP1, SPC24). Furthermore, any of the 4 parameters (prevalidated gene expression signature, TILs, CD3, and in particular MI) improved the ability of Tumor, Node, Metastasis (TNM) staging to predict postrecurrence survival; MI was the most significant contributor (HR = 2.13, P = 0.0008). An immune response gene expression signature and presence of TILs and CD3+ cells signify immune surveillance as a mechanism for prolonged survival in these patients and indicate improved patient subcategorization beyond current TNM staging.