Bevacizumab is the molecular-targeted agent used for the antiangiogenic therapy of metastatic colorectal cancer. But some patients are resistant to bevacizumab, it needs an effective biomarker to predict the prognosis and responses of metastatic colorectal cancer (mCRC) to bevacizumab therapy. In this work, we developed a qualitative transcriptional signature to individually predict the response of bevacizumab in patients with mCRC. First, using mCRC samples treated with bevacizumab, we detected differentially expressed genes between response and nonresponse groups. Then, the gene pairs, consisting of at least one differentially expressed gene, with stable relative expression orderings in the response samples but reversal stable relative expression orderings in the nonresponse samples were identified, denoted as pairs-bevacizumab. Similarly, we screened the gene pairs significantly associated with primary tumor locations, donated as pairs-LR. Among the overlapped gene pairs between the pairs-bevacizumab and pairs-LR, we adopted a feature selection process to extract gene pairs that reached the highest F-score for predicting bevacizumab response status in mCRC as the final gene pair signature (GPS), denoted as 64-GPS. In two independent datasets, the predicted response group showed significantly better overall survival than the nonresponse group (P = 6.00e−4 in GSE72970; P = 0.04 in TCGA). Genomic analyses showed that the predicted response group was characterized by frequent copy number alternations, whereas the nonresponse group was characterized by hypermutation. In conclusion, 64-GPS was an objective and robust predictive signature for patients with mCRC treated with bevacizumab, which could effectively assist in the decision of clinical therapy.

中文翻译：

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用于预测转移性结直肠癌中贝伐单抗的预后和反应的定性转录特征

贝伐单抗是用于转移性结直肠癌抗血管生成治疗的分子靶向药物。但部分患者对贝伐单抗耐药，需要一种有效的生物标志物来预测转移性结直肠癌（mCRC）对贝伐单抗治疗的预后和反应。在这项工作中，我们开发了一种定性转录特征来单独预测贝伐单抗对 mCRC 患者的反应。首先，使用贝伐单抗处理的 mCRC 样本，我们检测到反应组和无反应组之间的差异表达基因。然后，鉴定由至少一个差异表达基因组成的基因对，在响应样本中具有稳定的相对表达顺序，但在无响应样本中具有相反的稳定相对表达顺序，表示为对-贝伐单抗。相似地，我们筛选了与原发肿瘤位置显着相关的基因对，作为对-LR 捐赠。在pairs-bevacizumab和pairs-LR之间重叠的基因对中，我们采用特征选择过程来提取达到最高F-score的基因对，用于预测mCRC中贝伐珠单抗的反应状态作为最终的基因对特征（GPS），表示作为 64-GPS。在两个独立的数据集中，预测反应组的总生存率显着优于无反应组（GSE72970 中 P = 6.00e-4；TCGA 中 P = 0.04）。基因组分析表明，预测反应组的特征是频繁的拷贝数交替，而无反应组的特征是超突变。总之，对于接受贝伐珠单抗治疗的 mCRC 患者，64-GPS 是一个客观且可靠的预测特征，