Thioredoxin Reductase as a Novel and Efficient Plasma Biomarker for the Detection of Non-Small Cell Lung Cancer: a Large-scale, Multicenter study

Abstract

There is an increased demand for efficient biomarkers for the diagnosis of non-small cell lung cancer (NSCLC). This study aimed to evaluate plasma levels of TrxR activity in a large population to confirm its validity and efficacy in NSCLC diagnosis. Blood samples were obtained from 1922 participants (638 cases of NSCLC, 555 cases of benign lung diseases (BLDs) and 729 sex- and age-matched healthy controls). The plasma levels of TrxR activity in patients with NSCLC (15.66 ± 11.44 U/ml) were significantly higher (P < 0.01) than in patients with BLDs (6.27 ± 3.78 U/ml) or healthy controls (2.05 ± 1.86 U/ml). The critical value of plasma TrxR activity levels for diagnosis of NSCLC was set at 10.18 U/ml, with a sensitivity of 71.6% and a specificity of 91.9%. The combination of NSE, CEA, CA19-9, Cyfra21-1, and TrxR was more effective for NSCLC diagnosis (sensitivity and specificity in the training set: 85.6%, 90.2%; validation set: 86.2%, 92.4%) than was each biomarker individually (P < 0.001). TrxR can also efficiently distinguish the metastatic status of the tumor, and it can further differentiate between various histological differentiations. Together, plasma TrxR activity was identified as a convenient, non-invasive, and efficient biomarker for the diagnosis of NSCLCs, particularly for discriminating between metastatic and non-metastatic tumors, or for histologic differentiation.

Figure 1

Scatter plot of the distribution of plasma TrxR activity levels. (A–C) The plasma levels of TrxR activity from individuals in the training (A), validation (B), and whole (C) sets. (D–F) The plasma levels of TrxR activity from patients with NSCLC in the training (D), validation (E), and whole (F) sets. The black horizontal lines are median values. P values were determined by the Mann–Whitney U test.

Figure 2

(A,B) ROC curve analyses of TrxR activity levels for the differentiation of NSCLC and BLD cases in the training (A) and validation (B) sets. (C,D) ROC curve analyses of TrxR activity levels for BLD cases vs. healthy controls in the training (C) and validation (D) sets. (E,F) ROC curve analyses of NSE, Cyfra21-1, CA19-9, CEA and TrxR and the combinations thereof for the differentiation of NSCLC and BLD cases in the training (E) and validation (F) sets. (G,H) ROC curve analyses of NSE, Cyfra21-1, CA19-9, CEA and TrxR and the combinations thereof for NSCLC patients vs. those with BLDs and healthy controls in the training (G) and validation (H) sets.

Figure 3

(A) Scatter plot of the distribution of plasma TrxR activity levels in metastatic and non-metastatic NSCLC. (B) ROC curve analyses of TrxR activity levels for the differentiation of metastatic NSCLC from non-metastatic NSCLC. (C) The plasma levels of TrxR activity of NSCLC with various histologic differentiations.