Ewing Tumors That Do Not Overexpress BMI-1 Are a Distinct Molecular Subclass with Variant Biology: A Report from the Children's Oncology Group
Ewing Tumors That Do Not Overexpress BMI-1 Are a Distinct Molecular Subclass with Variant Biology: A Report from the Children's Oncology Group
复制标题
DOI：
10.1158/1078-0432.ccr-10-1417
复制
发表时间：
2011-01-01
影响因子：
11.5
通讯作者：
Lawlor, Elizabeth R.
中科院分区：
文献类型：
--
作者：
Cooper, Aaron;van Doorninck, John;Lawlor, Elizabeth R.
目的：尤文氏肉瘤家族肿瘤（ESFT）是一种侵袭性肿瘤，推测其起源于干细胞，需要预后生物标志物和新的治疗方法。在一些人类癌症中，多梳蛋白BMI-1的高表达与预后不良有关。我们评估了BMI-1表达水平在ESFT中的潜在临床意义。实验设计：通过免疫染色评估130例肿瘤中BMI-1的表达，并确定其与临床特征和预后的关系。利用微阵列和基因特异性富集分析鉴定的差异激活典型通路，比较了bmi -1低和bmi -1高肿瘤的分子特征。使用磷酸化蛋白的自动定量分析来评估途径激活的相对水平。采用MTS[3-（4,5二甲基噻唑-2-基）-5-（3-羧基甲氧基苯基）-2-（4-磺苯基）- 2h -四氮唑]测定对IGF1-R抑制的敏感性。结果：BMI-1在绝大多数ESFTs中过表达。然而，在20%的病例中，BMI-1水平很低甚至检测不到。值得注意的是，尽管高bmi -1和低bmi -1肿瘤的临床表现和结局相似，但全基因组表达阵列分析显示，它们各自的基因表达谱存在显著差异。基因特异性富集分析发现，与bmi -1高的肿瘤相比，bmi -1低的肿瘤中几种与癌症相关的典型生物学途径，包括IGF1、mTOR和WNT，显著下调。与这些体内数据一致，在体外，与bmi -1高的ESFT细胞相比，bmi -1低的ESFT细胞对IGF1-R抑制的反应减弱。结论：不过度表达BMI-1的ESFT代表了一种新的亚类，具有独特的分子谱，并改变了对癌症相关生物学途径的激活和依赖。临床癌症研究；17 (1);56 - 66。(c) 2010年aacr。
Purpose: Ewing sarcoma family tumors (ESFT) are aggressive tumors of putative stem cell origin for which prognostic biomarkers and novel treatments are needed. In several human cancers, high expression of the polycomb protein BMI-1 is associated with poor outcome. We have assessed the potential clinical significance of BMI-1 expression level in ESFT.Experimental Design: BMI-1 expression was assessed in 130 tumors by immunostaining and associations with clinical features and outcome determined. The molecular signatures of BMI-1-low and BMI-1high tumors were compared using microarrays and differentially activated canonical pathways identified by gene-specific enrichment analysis. Automated quantitative analysis of phosphoproteins was used to assess relative levels of pathway activation. Sensitivity to IGF1-R inhibition was determined using MTS [3-(4,5dimethylthiazol- 2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assays.Results: BMI-1 is overexpressed by the vast majority of ESFTs. However, in 20% of cases, BMI-1 levels are low to undetectable. Significantly, although clinical presentation and outcome were similar between BMI1- high and BMI-1-low tumors, whole genome expression array analysis showed marked differences in their respective gene expression profiles. Gene-specific enrichment analysis identified that several cancerassociated canonical biological pathways, including IGF1, mTOR, and WNT, are significantly downregulated in BMI-1-low compared with BMI-1-high tumors. Consistent with these in vivo data, the response to IGF1-R inhibition in vitro was diminished in BMI-1-low compared with BMI-1-high ESFT cells.Conclusion: ESFT that do not overexpress BMI-1 represent a novel subclass with a distinct molecular profile and altered activation of and dependence on cancer-associated biological pathways. Clin Cancer Res; 17(1); 56-66. (C) 2010 AACR.