1q gain and CDT2 overexpression underlie an aggressive and highly proliferative form of Ewing sarcoma
1q gain and CDT2 overexpression underlie an aggressive and highly proliferative form of Ewing sarcoma
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DOI：
10.1038/onc.2011.317
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发表时间：
2012-03-01
期刊：
影响因子：
8
通讯作者：
de Alava, E.
中科院分区：
文献类型：
--
作者：
Mackintosh, C.;Ordonez, J. L.;de Alava, E.
尽管对EWS-ETS融合的作用进行了广泛的描述，但对继发性遗传改变及其对Ewing肉瘤（ES）的临床贡献知之甚少。研究表明，EWS-ETS的分子结构缺乏预后价值。此外，CDKN2A缺失和TP53突变尽管预后较差，但并不常见。在这种情况下，确定具有显著普遍性的继发性遗传改变可能有助于理解最具侵袭性ES形式的分子机制。我们通过阵列比较基因组杂交筛选了67组ES肿瘤的拷贝数改变。在31%的肿瘤样本中检测到1q增益（1qG），发现与复发和较差的总生存期和无病生存期显著相关，并显示出独立于经典临床参数的预后价值。对属于一个独立肿瘤集（n = 37）的表达数据集的重新分析不仅验证了这一发现，而且还使我们确定了1qG ES肿瘤中严重细胞周期失调的转录组学特征。同样，Ki-67免疫组化检测到该肿瘤亚群中较高的增殖率。CDT2是一个位于1q的候选基因，编码一种参与泛素连接酶活性的蛋白，在1qG ES肿瘤中显著过表达，该基因在体外和体内得到验证，证明了其对这种分子和临床表型的主要贡献。这项针对105个ES肿瘤的综合基因组研究总体上显示了1qG和CDT2过表达作为预后生物标志物的潜在价值，也为已有的靶向蛋白泛素机制的新治疗化合物的应用提供了理论依据。中华肿瘤杂志，2012,31,1287-1298；doi: 10.1038 / onc.2011.317;2011年8月8日在线发布
Despite extensive characterization of the role of the EWS-ETS fusions, little is known about secondary genetic alterations and their clinical contribution to Ewing sarcoma (ES). It has been demonstrated that the molecular structure of EWS-ETS lacks prognostic value. Moreover, CDKN2A deletion and TP53 mutation, despite carrying a poor prognosis, are infrequent. In this scenario identifying secondary genetic alterations with a significant prevalence could contribute to understand the molecular mechanisms underlying the most aggressive forms of ES. We screened a 67 ES tumor set for copy number alterations by array comparative genomic hybridization. 1q gain (1qG), detected in 31% of tumor samples, was found markedly associated with relapse and poor overall and disease-free survival and demonstrated a prognostic value independent of classical clinical parameters. Reanalysis of an expression dataset belonging to an independent tumor set (n = 37) not only validated this finding but also led us to identify a transcriptomic profile of severe cell cycle deregulation in 1qG ES tumors. Consistently, a higher proliferation rate was detected in this tumor subset by Ki-67 immunohistochemistry. CDT2, a 1q-located candidate gene encoding a protein involved in ubiquitin ligase activity and significantly overexpressed in 1qG ES tumors, was validated in vitro and in vivo proving its major contribution to this molecular and clinical phenotype. This integrative genomic study of 105 ES tumors in overall renders the potential value of 1qG and CDT2 overexpression as prognostic biomarkers and also affords a rationale for the application of already available new therapeutic compounds selectively targeting the protein-ubiquitin machinery. Oncogene (2012) 31, 1287-1298; doi: 10.1038/onc.2011.317; published online 8 August 2011