Midkine Expression as a Candidate Biomarker to Predict the Recurrence of Stage IA Lung Adenocarcinoma.

BACKGROUND: Early recurrence limits the long-term survival of postoperative patients with stage IA lung adenocarcinoma (LUAD). This study aims to risk-stratify postoperative stage IA LUAD by means of the expression of Midkine (MDK). MATERIALS AND METHODS: We collected surgical samples from 62 patients with stage IA LUAD, of which 30 patients had early recurrence and others without. Intratumoral and peritumoral MDK expression were measured by immunohistochemistry staining. We also analyzed the MDK expression of stage IA LUAD from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus repository. RESULTS: The intratumoral MDK was significantly overexpressed in patients with early recurrence (p < 0.001). Kaplan-Meier survival analysis revealed that patients with higher intratumoral MDK expression had poor recurrence-free survival (p < 0.001) and overall survival (p = 0.004). Univariate Cox regression analysis indicated that intratumoral MDK expression significantly increased the risk of recurrence (hazard ratio [HR] 1.408 (1.076-1.842), p = 0.013) and death (HR 1.888 [1.127-3.162], p = 0.016). Stepwise Cox regression analysis revealed that smoking (HR 2.944 [1.419-6.107], p = 0.004), intratumoral MDK expression (HR 1.316 [1.037-1.669], p = 0.024), and EGFR mutation (HR 2.407 [1.110-5.221], p = 0.026) were independent prognostic factors for early recurrence. In TCGA data set, the MDK expression significantly increased the risk of recurrence (HR 1.559 [1.035-2.349], p = 0.034), and patients with higher MDK expression had worse disease-free survival (p = 0.024). In GSE31210, the MDK expression significantly increased the risk of recurrence (HR 2.617 [1.791-3.824], p < 0.001) and death (HR 2.495 [1.429-4.356], p = 0.001), whereas patients with higher MDK expression also had worse recurrence-free survival (p = 0.006) and overall survival (p < 0.001). CONCLUSION: MDK was considered a putative candidate for predicting early recurrence in patients with stage IA LUAD.