MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
International Agency for Research on Cancer (IARC), Lyon, France.
Cancer Res. 2021 Jul 1;81(13):3738-3748. doi: 10.1158/0008-5472.CAN-20-3454. Epub 2021 Feb 11.
Increasing evidence points to a role for inflammation in lung carcinogenesis. A small number of circulating inflammatory proteins have been identified as showing elevated levels prior to lung cancer diagnosis, indicating the potential for prospective circulating protein concentration as a marker of early carcinogenesis. To identify novel markers of lung cancer risk, we measured a panel of 92 circulating inflammatory proteins in 648 prediagnostic blood samples from two prospective cohorts in Italy and Norway (women only). To preserve the comparability of results and protect against confounding factors, the main statistical analyses were conducted in women from both studies, with replication sought in men (Italian participants). Univariate and penalized regression models revealed for the first time higher blood levels of CDCP1 protein in cases that went on to develop lung cancer compared with controls, irrespective of time to diagnosis, smoking habits, and gender. This association was validated in an additional 450 samples. Associations were stronger for future cases of adenocarcinoma where CDCP1 showed better explanatory performance. Integrative analyses combining gene expression and protein levels of CDCP1 measured in the same individuals suggested a link between CDCP1 and the expression of transcripts of LRRN3 and SEM1. Enrichment analyses indicated a potential role for CDCP1 in pathways related to cell adhesion and mobility, such as the WNT/β-catenin pathway. Overall, this study identifies lung cancer-related dysregulation of CDCP1 expression years before diagnosis. SIGNIFICANCE: Prospective proteomics analyses reveal an association between increased levels of circulating CDCP1 and lung carcinogenesis irrespective of smoking and years before diagnosis, and integrating gene expression indicates potential underlying mechanisms..
越来越多的证据表明炎症在肺癌发生中起作用。有少数循环炎症蛋白被确定在肺癌诊断前水平升高，表明前瞻性循环蛋白浓度作为早期癌变标志物的潜力。为了确定肺癌风险的新标志物，我们在意大利和挪威的两个前瞻性队列的 648 个预诊断血样中测量了 92 种循环炎症蛋白的一个面板（仅限女性）。为了保持结果的可比性并防止混杂因素，主要的统计分析在两项研究中的女性中进行，并在男性（意大利参与者）中进行了复制。单变量和惩罚回归模型首次揭示了与对照组相比，发展为肺癌的病例中 CDCP1 蛋白的血液水平更高，而与诊断时间、吸烟习惯和性别无关。在另外 450 个样本中验证了这种关联。对于未来的腺癌病例，CDCP1 的关联更强，CDCP1 显示出更好的解释性能。对同一人群中测量的 CDCP1 基因表达和蛋白水平进行的综合分析表明，CDCP1 与 LRRN3 和 SEM1 转录本的表达之间存在联系。富集分析表明 CDCP1 在与细胞黏附和迁移相关的途径中可能具有潜在作用，例如 WNT/β-catenin 途径。总的来说，这项研究在诊断前数年确定了与肺癌相关的 CDCP1 表达失调。意义：前瞻性蛋白质组学分析表明，循环 CDCP1 水平升高与肺癌发生之间存在关联，无论吸烟和诊断前时间如何，整合基因表达表明潜在的潜在机制。
