A network-based predictive gene-expression signature for adjuvant chemotherapy benefit in stage II colorectal cancer.
A network-based predictive gene-expression signature for adjuvant chemotherapy benefit in stage II colorectal cancer.
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基于网络的预测基因表达特征对 II 期结直肠癌辅助化疗的益处
DOI：
10.1186/s12885-017-3821-4
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发表时间：
2017-12-13
期刊：
影响因子：
3.8
通讯作者：
Chen C
中科院分区：
文献类型：
--
作者：
Cao B;Luo L;Feng L;Ma S;Chen T;Ren Y;Zha X;Cheng S;Zhang K;Chen C
二期结直肠癌(CRC)辅助化疗的临床益处存在争议。本研究旨在探索新的基因标记来预测II期结直肠癌术后以5-FU为基础的治疗效果。分析两个数据集(训练数据集，n = 212；验证数据集，n = 85)中II期CRC的基因表达谱，以确定该指标。采用基因表达和蛋白质相互作用(PPI)网络相结合的系统方法来开发预测性签名。采用Kaplan-Meier曲线和Cox比例风险模型分析辅助化疗的生存效益。用shRNA敲除的实验证实了本研究中识别的签名。在训练数据集中，我们识别了44个PPI子模块，通过这些子模块，我们将患者分为两个具有不同化疗益处的聚类(1和2)。建立了11个PPI子模块(11-PPI-Mod)的预测值来区分两个亚组，总体准确率为90.1%。该签名是在外部验证数据集中独立验证的。Kaplan-Meier曲线显示，在第1组中接受辅助化疗的患者的结果有所改善，但在第2组中接受辅助化疗的患者的存活率更差。在训练数据集和验证数据集中都发现了类似的结果。多变量COX回归显示，在训练数据集(rfS，p = 0.007；OS，p = 0.006)和验证数据集(rfS，p = 0.002)中，11-ppi-mod签名和辅助治疗之间存在交互作用。从签名中我们发现PTGES基因在对5-FU耐药较强的CRC细胞中上调。PTGES表达下调表明5-FU诱导的大肠癌细胞生长抑制和凋亡标志物表达上调。只有一小部分II期结直肠癌患者可以从辅助治疗中受益。11-PPI-MOD作为一个潜在的预测指标，可能有助于区分这一预后良好的亚组。本文的在线版本(10.1186/s12885-0173821-4)包含向授权用户提供的补充材料。
The clinical benefit of adjuvant chemotherapy for stage II colorectal cancer (CRC) is controversial. This study aimed to explore novel gene signature to predict outcome benefit of postoperative 5-Fu-based therapy in stage II CRC. Gene-expression profiles of stage II CRCs from two datasets with 5-Fu-based adjuvant chemotherapy (training dataset, n = 212; validation dataset, n = 85) were analyzed to identify the indicator. A systemic approach by integrating gene-expression and protein-protein interaction (PPI) network was implemented to develop the predictive signature. Kaplan-Meier curves and Cox proportional hazards model were used to determine the survival benefit of adjuvant chemotherapy. Experiments with shRNA knock-down were carried out to confirm the signature identified in this study. In the training dataset, we identified 44 PPI sub-modules, by which we separate patients into two clusters (1 and 2) having different chemotherapeutic benefit. A predictor of 11 PPI sub-modules (11-PPI-Mod) was established to discriminate the two sub-groups, with an overall accuracy of 90.1%. This signature was independently validated in an external validation dataset. Kaplan-Meier curves showed an improved outcome for patients who received adjuvant chemotherapy in Cluster 1 sub-group, but even worse survival for those in Cluster 2 sub-group. Similar results were found in both the training and the validation dataset. Multivariate Cox regression revealed an interaction effect between 11-PPI-Mod signature and adjuvant therapy treatment in the training dataset (RFS, p = 0.007; OS, p = 0.006) and the validation dataset (RFS, p = 0.002). From the signature, we found that PTGES gene was up-regulated in CRC cells which were more resistant to 5-Fu. Knock-down of PTGES indicated a growth inhibition and up-regulation of apoptotic markers induced by 5-Fu in CRC cells. Only a small proportion of stage II CRC patients could benefit from adjuvant therapy. The 11-PPI-Mod as a potential predictor could be helpful to distinguish this sub-group with favorable outcome. The online version of this article (10.1186/s12885-017-3821-4) contains supplementary material, which is available to authorized users.
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影响因子：
3.4
作者：
Kelley RK;Venook AP
通讯作者：
Venook AP
影响因子：
4.7
作者：
Lee, James J.;Natsuizaka, Mitsuteru;Nakagawa, Hiroshi
通讯作者：
Nakagawa, Hiroshi
影响因子：
21.3
作者：
通讯作者：
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影响因子：
8
作者：
Ma, S. Q.;Cao, B. R.;Chen, C. M.
通讯作者：
Chen, C. M.
DOI：
10.1016/j.bbrc.2012.12.118
发表时间：
2013-02-08
影响因子：
3.1
作者：
Ma, Yimin;Ren, Yongxin;Han, Ethan Q.;Li, Huiwu;Chen, Di;Jacobs, Joshua J.;Gitelis, Steven;O'Keefe, Regis J.;Konttinen, Yrjo T.;Yin, Guoyong;Li, Tian-Fang
通讯作者：
Li, Tian-Fang