Abstract
Purpose: In this study, we aimed to investigate the potential prognostic molecular marker in patients with "pan-driver-gene-negative" lung adenocarcinoma (PDGN-LUAD). LUAD patients who were negative for mutations in EGFR, KRAS, BRAF, HER2, MET, ALK, RET and ROS1 were identified as PDGN-LUAD. Methods: In the screening phase, we profiled the mRNA expression levels in 52 paired PDGN-LUAD tumor tissues and adjacent normal tissues using a genome-wide microarray, and the results revealed that the expression level of dishevelled segment polarity protein 3 (DVL3) was higher in PDGN-LUAD tumor tissues than in normal lung tissues. Then, we enrolled 626 PDGN-LUAD patients from three independent hospital centers and divided them into a training cohort, an internal validation cohort and two external validation cohorts. In the training cohort, tissue microarrays (TMAs) were used to confirm the protein expression level of DVL3. Statistical methods were applied to explore the prognostic role of DVL3. Results: The results indicated that the level of DVL3 could be used to classify patients with PDGN-LUAD in the training cohort into a high-risk group (high expression level of DVL3) and a low-risk group (low expression level of DVL3). In the training cohort, high-risk patients had shorter overall survival (OS) times (hazard ratio [HR] 2.27; 95% CI, 1.57-2.97; p<0.001) than low-risk patients. In the validation phase, the performance of DVL3 as a prognostic marker was successfully validated in the internal and external cohorts. Conclusions: In conclusion, DVL3 is an important prognostic indicator for PDGN-LUAD and may provide new insights into the treatment of PDGN-LUAD.