Integrative genomics analysis identifies candidate drivers at 3q26-29 amplicon in squamous cell carcinoma of the lung.
Integrative genomics analysis identifies candidate drivers at 3q26-29 amplicon in squamous cell carcinoma of the lung.
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DOI：
10.1158/1078-0432.ccr-13-0594
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发表时间：
2013-10-15
期刊：
影响因子：
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通讯作者：
Massion PP
中科院分区：
文献类型：
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作者：
Wang J;Qian J;Hoeksema MD;Zou Y;Espinosa AV;Rahman SM;Zhang B;Massion PP
染色体3q 26 -29是肺鳞状细胞癌基因组扩增的关键区域。识别该区域的候选驱动因素可能有助于揭示肺SCC发病机制的新机制和潜在的新靶点。我们对包含总共593个人类原发性SCC肿瘤样本的7个独立数据集进行了荟萃分析，以鉴定3q 26 -29扩增子中的共有候选驱动因子。通过整合蛋白质-蛋白质相互作用网络信息，我们进一步筛选出可能在网络中共同发挥作用的候选者。使用RNAi敲低和细胞活力测定验证计算预测的候选物。使用生存分析在52个肺SCC肿瘤的独立队列中评价实验支持的驱动器的临床相关性。荟萃分析确定了20个共识候选者，其中4个（SENP 2，DCUN 1D 1，DVL 3和UBXN 7）参与了一个小的蛋白质-蛋白质相互作用网络。敲除这四种蛋白中的任何一种都导致3q 26 -29扩增的SCC的细胞生长抑制。此外，SENP 2的敲低导致最显著的细胞生长抑制和DCUN 1D 1和DVL 3的下调。重要的是，由SENP 2、DCUN 1D 1和DVL 3组成的基因表达特征将患者分为对辅助化疗具有不同反应的亚组。总之，我们的研究结果表明，SENP 2，DCUN 1D 1和DVL 3是SCC 3q 26 -29扩增子中的候选驱动基因，为疾病进展的分子机制提供了新的见解，并可能对肺SCC的管理具有重要意义。
Chromosome 3q26-29 is a critical region of genomic amplification in lung squamous cell carcinomas (SCCs). Identification of candidate drivers in this region could help uncover new mechanisms in the pathogenesis and potentially new targets in SCC of the lung. We performed a meta-analysis of seven independent data sets containing a total of 593 human primary SCC tumor samples to identify consensus candidate drivers in 3q26-29 amplicon. Through integrating protein-protein interaction network information, we further filtered for candidates that may function together in a network. Computationally predicted candidates were validated using RNAi knock down and cell viability assays. Clinical relevance of the experimentally supported drivers was evaluated in an independent cohort of 52 lung SCC tumors using survival analysis. The meta-analysis identified 20 consensus candidates, among which four (SENP2, DCUN1D1, DVL3 and UBXN7) were involved in a small protein-protein interaction network. Knocking down any of the four proteins led to cell growth inhibition of the 3q26-29 amplified SCC. Moreover, knocking down of SENP2 resulted in the most significant cell growth inhibition and downregulation of DCUN1D1 and DVL3. Importantly, a gene expression signature composed of SENP2, DCUN1D1 and DVL3 stratified patients into subgroups with different response to adjuvant chemotherapy. Together, our findings show that SENP2, DCUN1D1 and DVL3 are candidate driver genes in the 3q26-29 amplicon of SCC, providing novel insights into the molecular mechanisms of disease progression and may have significant implication in the management of SCC of the lung.