Sun Xiaohui, Shu Xiao-Ou, Lan Qing, Laszkowska Monika, Cai Qiuyin, Rothman Nathaniel, Wen Wanqing, Zheng Wei, Shu Xiang
Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10017, USA.
Department of Epidemiology, Zhejiang Chinese Medical University, Hangzhou 310053, China.
Cancers (Basel). 2022 Jul 3;14(13):3261. doi: 10.3390/cancers14133261.
Proteomics-based technologies are emerging tools used for cancer biomarker discovery. Limited prospective studies have been conducted to evaluate the role of circulating proteins in colorectal cancer (CRC) development.
A two-stage case-control proteomics study nested in the Shanghai Women's Health Study was conducted. A total of 1104 circulating proteins were measured in the discovery phase, consisting of 100 incident CRC cases and 100 individually matched controls. An additional 60 case-control pairs were selected for validation. Protein profiling at both stages was completed using the Olink platforms. Conditional logistic regression was used to evaluate the associations between circulating proteins and CRC risk. The elastic net method was employed to develop a protein score for CRC risk.
In the discovery set, 27 proteins showed a nominally significant association with CRC risk, among which 22 were positively and 5 were inversely associated. Six of the 27 protein markers were significantly associated with CRC risk in the validation set. In the analysis of pooled discovery and validation sets, odds ratios (ORs) per standard deviation (SD) increase in levels of these proteins were 1.54 (95% confidence interval (CI): 1.15-2.06) for CD79B; 1.71 (95% CI: 1.24-2.34) for DDR1; 2.04 (95% CI: 1.39-3.01) for EFNA4; 1.54 (95% CI: 1.16-2.02) for FLRT2; 2.09 (95% CI: 1.47-2.98) for LTA4H and 1.88 (95% CI: 1.35-2.62) for NCR1. Sensitivity analyses showed consistent associations for all proteins with the exclusion of cases diagnosed within the first two years after the cohort enrollment, except for CD79B. Furthermore, a five-protein score was developed based on the six proteins identified and showed significant associations with CRC risk in both discovery and validation sets (Discovery: OR = 2.46, 95% CI: 1.53-3.95; validation: OR = 4.16, 95% CI: 1.92-8.99).
A panel of five protein markers was identified as potential biomarkers for CRC risk. Our findings provide novel insights into the etiology of CRC and may facilitate the risk assessment of the malignancy.
基于蛋白质组学的技术是用于发现癌症生物标志物的新兴工具。关于循环蛋白在结直肠癌（CRC）发生发展中的作用，所开展的前瞻性研究有限。
在上海女性健康研究中开展了一项两阶段的病例对照蛋白质组学研究。在发现阶段共检测了1104种循环蛋白，包括100例初发CRC病例和100例个体匹配的对照。另外选取60对病例对照进行验证。两个阶段的蛋白质谱分析均使用Olink平台完成。采用条件逻辑回归评估循环蛋白与CRC风险之间的关联。运用弹性网络法制定CRC风险的蛋白质评分。
在发现集中，27种蛋白与CRC风险呈名义上显著的关联，其中22种呈正相关，5种呈负相关。在验证集中，27种蛋白标志物中有6种与CRC风险显著相关。在合并的发现集和验证集分析中，这些蛋白水平每增加一个标准差（SD）的比值比（OR）分别为：CD79B为1.54（95%置信区间（CI）：1.15 - 2.06）；DDR1为1.71（95%CI：1.24 - 2.34）；EFNA4为2.04（95%CI：1.39 - 3.01）；FLRT2为1.54（95%CI：1.16 - 2.02）；LTA4H为2.09（95%CI：1.47 - 2.98）；NCR1为1.88（95%CI：1.35 - 2.62）。敏感性分析显示，除CD79B外，排除队列入组后前两年内确诊的病例后，所有蛋白的关联均一致。此外，基于所确定的6种蛋白制定了一个五蛋白评分，该评分在发现集和验证集中均与CRC风险显著相关（发现集：OR = 2.46，95%CI：1.53 - 3.95；验证集：OR = 4.16，95%CI：1.92 - 8.99）。
一组五种蛋白标志物被确定为CRC风险的潜在生物标志物。我们的研究结果为CRC的病因学提供了新的见解，并可能有助于该恶性肿瘤的风险评估。
