Authors' Affiliations: Department of Biomedical Informatics, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine; and Veterans Affairs, Tennessee Valley Health Care Systems, Nashville, Tennessee.
Clin Cancer Res. 2013 Oct 15;19(20):5580-90. doi: 10.1158/1078-0432.CCR-13-0594. Epub 2013 Aug 1.
Chromosome 3q26-29 is a critical region of genomic amplification in lung squamous cell carcinomas (SCC). 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 conducted a meta-analysis of seven independent datasets containing a total of 593 human primary SCC 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 RNA interference (RNAi) knockdown and cell viability assays. Clinical relevance of the experimentally supported drivers was evaluated in an independent cohort of 52 lung SCC patients using survival analysis.
The meta-analysis identified 20 consensus candidates, among which four (SENP2, DCUN1D1, DVL3, and UBXN7) are 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.
染色体 3q26-29 是肺鳞癌（SCC）基因组扩增的关键区域。在该区域中鉴定候选驱动基因有助于揭示疾病发生的新机制，并可能为肺鳞癌提供新的治疗靶点。
我们对包含 593 个人类原发性 SCC 样本的七个独立数据集进行了荟萃分析，以确定 3q26-29 扩增子中的共识候选驱动基因。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作用的候选基因。使用 RNA 干扰（RNAi）敲低和细胞活力测定法验证计算预测的候选基因。在 52 例肺 SCC 患者的独立队列中，使用生存分析评估实验支持的驱动基因的临床相关性。
荟萃分析确定了 20 个共识候选基因，其中 4 个（SENP2、DCUN1D1、DVL3 和 UBXN7）参与了一个小的蛋白质-蛋白质相互作用网络。敲低这四个蛋白中的任何一个都导致 3q26-29 扩增 SCC 的细胞生长抑制。此外，敲低 SENP2 导致最显著的细胞生长抑制和 DCUN1D1 和 DVL3 的下调。重要的是，由 SENP2、DCUN1D1 和 DVL3 组成的基因表达谱将患者分为对辅助化疗反应不同的亚组。
总之，我们的研究结果表明，SENP2、DCUN1D1 和 DVL3 是 SCC 3q26-29 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，并可能对肺鳞癌的治疗具有重要意义。
