Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA.
Division of Hematology and Oncology, University of North Carolina, Chapel Hill, NC, USA.
Ann Surg Oncol. 2017 Dec;24(13):4051-4058. doi: 10.1245/s10434-017-6054-5. Epub 2017 Sep 21.
The directed study of the functional proteome in colorectal cancer (CRC) has identified critical protein markers and signaling pathways; however, the prognostic relevance of many of these proteins remains unclear.
We determined the prognostic implications of the functional proteome in 263 CRC tumor samples from patients treated at MD Anderson Cancer Center (MDACC) and 462 patients from The Cancer Genome Atlas (TCGA) to identify patterns of protein expression that drive tumorigenesis. A total of 163 validated proteins were analyzed by reverse phase protein array (RPPA). Unsupervised hierarchical clustering of the tumor proteins from the MDACC cohort was performed, and clustering was validated using RPPA data from TCGA CRC. Cox regression was used to identify predictors of tumor recurrence.
Clustering revealed dichotomization, with subtype A notable for a high epithelial-mesenchymal transition (EMT) protein signature, while subtype B was notable for high Akt/TSC/mTOR pathway components. Survival data were only available for the MDACC cohort and were used to evaluate prognostic relevance of these protein signatures. Group B demonstrated worse relapse-free survival (hazard ratio 2.11, 95% confidence interval 1.04-4.27, p = 0.039), although there was no difference in known genomic drivers between the two proteomic groups. Proteomic grouping and stage were significant predictors of recurrence on multivariate analysis. Eight proteins were found to be significant predictors of tumor recurrence on multivariate analysis: Collagen VI, FOXO3a, INPP4B, LcK, phospho-PEA15, phospho-PRAS40, Rad51, phospho-S6.
CRC can be classified into distinct subtypes by proteomic features independent of common oncogenic driver mutations. Proteomic analysis has identified key biomarkers with prognostic importance, however these findings require further validation in an independent cohort.
在结直肠癌（CRC）中对功能蛋白质组的定向研究已经确定了关键的蛋白质标记物和信号通路；然而，其中许多蛋白质的预后相关性仍不清楚。
我们确定了 MD 安德森癌症中心（MDACC）263 例 CRC 肿瘤样本和癌症基因组图谱（TCGA）462 例患者的功能蛋白质组的预后意义，以确定驱动肿瘤发生的蛋白质表达模式。通过反相蛋白质阵列（RPPA）分析了 163 种经过验证的蛋白质。对 MDACC 队列的肿瘤蛋白进行无监督层次聚类，使用 TCGA CRC 的 RPPA 数据验证聚类。使用 Cox 回归确定肿瘤复发的预测因子。
聚类显示分为两型，A 型以高上皮-间充质转化（EMT）蛋白特征为特征，而 B 型以高 Akt/TSC/mTOR 通路成分为特征。生存数据仅可用于 MDACC 队列，并用于评估这些蛋白质特征的预后相关性。B 组的无复发生存率较差（危险比 2.11，95%置信区间 1.04-4.27，p=0.039），尽管两组蛋白质之间没有差异已知的基因组驱动因素。多变量分析显示，蛋白质组分组和分期是复发的显著预测因子。在多变量分析中，有 8 种蛋白质被发现是肿瘤复发的显著预测因子：胶原 VI、FOXO3a、INPP4B、LcK、磷酸化 PEA15、磷酸化 PRAS40、Rad51、磷酸化 S6。
CRC 可以通过独立于常见致癌驱动突变的蛋白质特征分为不同的亚型。蛋白质组分析已经确定了具有重要预后意义的关键生物标志物，然而这些发现需要在独立队列中进一步验证。
