Prospective Identification of Elevated Circulating CDCP1 in Patients Years before Onset of Lung Cancer

Abstract

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. See related commentary by Itzstein et al., p. 3441.

AXL/CDCP1/SRC axis confers acquired resistance to osimertinib in lung cancer

“…This is the first study to reveal the association of CDCP1 with acquired resistance to osimertinib in cancer cells. Recent prospective proteomics analysis by Dagnino et al has demonstrated that higher blood levels of CDCP1 protein are clearly associated with the risk of lung cancer 44 , suggesting the potential role of CDCP1 in onset of lung cancer. On the other hand, CDCP1 has been reported to enhance WNT/β-catenin signaling pathway through increased nuclear localization of β-catenin 45 .…”

CDCP1 Expression Is a Potential Biomarker of Poor Prognosis in Resected Stage I Non-Small-Cell Lung Cancer

“…Ikeda et al [28] conducted a multivariate Cox regression analysis of 200 lung adenocarcinoma patients and reported that high CDCP1 expression acts as an independent prognostic factor for OS and DFS. Dagnino et al [29] suggest that circulating serum levels of CDCP1 provide additional information on future lung cancer risk, especially in patients who had tobacco exposure. Although this study was different from our study in which they measured plasma CDCP1 levels, our results were similar in terms of the possibility of CDCP1 being an early diagnostic marker considering the high percentage of smoking patients in the CDCP1-positive group.…”

The Blood Proteome of Imminent Lung Cancer Diagnosis

“…At least eight of the 36 markers have been previously reported to be associated with lung cancer in pre-diagnostic samples, including several well-known tumor markers such as CEACAM5/CEA and CA-125/MUC-16, 34 as well as IL6, CDCP1, CXCL9 and CXCL13. [36][37][38] However, most of the 36 proteins are newly identified pre-diagnostic markers of lung cancer.…”

“…This may suggest a role for these markers in tumor progression or an immune or inflammation response in lung tissue. Notably, CDCP1 was previously associated with an increased risk of lung cancer in pre-diagnostic blood, 38 is overexpressed in lung cancer tissue, 51 and is associated with metastases and poor prognosis. [51][52][53][54]…”