MET expression and copy number heterogeneity in nonsquamous non-small cell lung cancer (nsNSCLC)
MET expression and copy number heterogeneity in nonsquamous non-small cell lung cancer (nsNSCLC)
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DOI：
10.18632/oncotarget.3976
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发表时间：
2015-06-30
期刊：
影响因子：
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通讯作者：
Arriola, Edurne
中科院分区：
文献类型：
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作者：
Casadevall, David;Gimeno, Javier;Arriola, Edurne
目的：我们的目的是评估MET瘤内异质性及其对基于生物标志物的患者选择的潜在影响以及MET activation.Methods的潜在替代生物标志物：我们的研究包括120例非鳞状非小细胞肺癌（nsNSCLC），其中47例被纳入组织微阵列（TMA）。选择四个形态学上不同的肿瘤区域来评估MET异质性。通过免疫组织化学（IHC）的MET阳性定义为高于中值H-评分和>50%的肿瘤细胞中+2/ +3染色强度（Metmab标准）。MET FISH阳性定义为MET/CEP 7比值>= 2.0和/或MET >= 5.0。MET染色模式（细胞质与膜）和间充质标记物作为MET activation.Results的替代物进行了研究：MET H评分中位数为140（范围0-400），47.8%的患者按Metmab标准呈MET阳性。8例（6.8%）MET FISH阳性，显示较高的H评分（p = 0.021）。在不同肿瘤区域中，高达40%的病例中，通过IHC检测的MET阳性发生变化，MET扩增率为25- 50%。细胞质MET染色和波形蛋白阳性预测生存率差（p = 0.042和0.047，分别）。结论：MET状态是高度异质性之间的不同nsNSCLC肿瘤领域，阻碍了适当的患者选择MET靶向治疗。MET细胞质染色和波形蛋白可能代表MET活化的替代标志物。
Objective: We aimed to assess MET intratumoral heterogeneity and its potential impact on biomarker-based patient selection as well as potential surrogate biomarkers of MET activation.Methods: Our study included 120 patients with non-squamous Non-small-cell Lung Cancer (nsNSCLC), of which 47 were incorporated in tissue microarrays (TMA). Four morphologically distinct tumor areas were selected to assess MET heterogeneity. MET positivity by immunohistochemistry (IHC) was defined as an above-median H-score and by +2/ +3 staining intensity in >50% of tumor cells (Metmab criteria). MET FISH positivity was defined by MET/CEP7 ratio >= 2.0 and/or MET >= 5.0. MET staining pattern (cytoplasmic vs. membranous) and mesenchymal markers were investigated as surrogates of MET activation.Results: Median MET H-score was 140 (range 0-400) and 47.8% of patients were MET positive by Metmab criteria. Eight cases (6.8%) were MET FISH positive and showed higher H-scores (p = 0.021). MET positivity by IHC changed in up to 40% of cases among different tumor areas, and MET amplification in 25-50%. Cytoplasmic MET staining and positivity for vimentin predicted poor survival (p = 0.042 and 0.047, respectively).Conclusions: MET status is highly heterogeneous among different nsNSCLC tumor areas, hindering adequate patient selection for MET-targeted therapies. MET cytoplasmic staining and vimentin might represent surrogate markers for MET activation.