Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.
Cancer Sci. 2018 Jun;109(6):1939-1948. doi: 10.1111/cas.13622. Epub 2018 May 23.
5-Fluorouracil (5-FU)-based adjuvant chemotherapy (ACT) is widely used for the treatment of colon cancer. Colon cancers with different primary tumor locations are clinically and molecularly distinct, implied through their response to 5-FU-based ACT. In this work, using 69 and 133 samples of patients with stage II-III right-sided and left-sided colon cancer (RCC and LCC) treated with post-surgery 5-FU-based ACT, we preselected gene pairs whose relative expression orderings were significantly correlated with the disease-free survival of patients by univariate Cox proportional hazards model. Then, from the identified prognostic-related gene pairs, a forward-stepwise selection algorithm was formulated to search for an optimal subset of gene pairs that resulted in the highest concordance index, referred to as the gene pair signature (GPS). We identified prognostic signatures, 3-GPS and 5-GPS, for predicting response to 5-FU-based ACT of patients with RCC and LCC, respectively, which were validated in independent datasets of GSE14333 and GSE72970. With the aid of the signatures, the transcriptional and genomic characteristics between the predicted responders and non-responders were explored. Notably, both in RCC and LCC, the predicted responders to 5-FU-based ACT were characterized by hypermutation, whereas the predicted non-responders were characterized by frequent copy number alternations. Finally, in comparison with the established relative expression ordering-based signature, which was developed without considering the differences between RCC and LCC, the newly proposed signatures had a better predictive performance. In conclusion, 3-GPS or 5-GPS can robustly predict response to 5-FU-based ACT for patients with RCC or LCC, respectively, in an individual level.
5-氟尿嘧啶（5-FU）为基础的辅助化疗（ACT）广泛用于治疗结肠癌。具有不同原发肿瘤位置的结肠癌在临床上和分子上是不同的，这表现在它们对 5-FU 为基础的 ACT 的反应上。在这项工作中，使用了 69 名和 133 名接受术后 5-FU 为基础的 ACT 治疗的 II-III 期右侧和左侧结肠癌（RCC 和 LCC）患者的样本，我们通过单变量 Cox 比例风险模型预先选择了基因对，其相对表达顺序与患者无病生存率显著相关。然后，从确定的预后相关基因对中，制定了一个前向逐步选择算法，以搜索导致最高一致性指数的基因对最佳子集，称为基因对特征（GPS）。我们分别确定了 3-GPS 和 5-GPS 两种预测 RCC 和 LCC 患者对 5-FU 为基础的 ACT 反应的预后特征，在 GSE14333 和 GSE72970 的独立数据集上进行了验证。借助这些特征，探讨了预测应答者和非应答者之间的转录组和基因组特征。值得注意的是，在 RCC 和 LCC 中，预测对 5-FU 为基础的 ACT 有反应的患者的特征是超突变，而预测无反应的患者的特征是频繁的拷贝数改变。最后，与未考虑 RCC 和 LCC 差异而开发的基于相对表达顺序的特征相比，新提出的特征具有更好的预测性能。总之，3-GPS 或 5-GPS 可以分别在个体水平上稳健地预测 RCC 或 LCC 患者对 5-FU 为基础的 ACT 的反应。
