GP88 (progranulin): a novel tissue and circulating biomarker for non-small cell lung carcinoma

Abstract

GP88 (progranulin) is a growth and survival factor implicated in tumorigenesis and drug resistance. Previous studies showed that GP88 was expressed in breast cancer tissue in inverse correlation with survival. This study evaluates GP88 tissue expression in localized/locally advanced lung cancer and GP88 serum levels in advanced disease. GP88 expression was determined by immunohistochemistry in tumor tissue from non-small cell lung carcinoma (NSCLC) patients, 85 with localized (stage I-II), and 40 with locally advanced disease (stage IIIa) and correlated with clinical outcome. Serum GP88 levels from stage IIIb/IV patients, quantified by enzyme immunoassay were compared with GP88 levels from patients with chronic obstructive pulmonary disease and healthy individuals. GP88 was expressed in more than 80% adenocarcinoma and squamous cell carcinoma in contrast to normal lung or small cell lung cancer. There was a statistically significant inverse association of GP88 expression (GP88 immunohistochemistry score, 3+ versus < 3+) with survival for patients with localized resected NSCLC with hazard ratio (HR) = 2.28 (P = .0076) for disease-free survival and HR = 2.17 (P = .014) for overall survival. A statistically significant decrease in progression-free survival (HR = 2.9; P = .022) for GP88 scores of 3+ versus less than 3+ was observed for stage IIIa after chemoradiotherapy. In addition, serum GP88 was significantly elevated in stage IIIb/IV NSCLC compared with control subjects (49.9 ng/mL versus 28.4 ng/mL; P < .0001). This is the first study demonstrating GP88 tissue and serum expression as a prognostic biomarker in localized and advanced disease. Future research will determine utility of monitoring GP88 and the potential of GP88 expression as a predictive marker for anti-GP88 therapeutics.

Keywords: GP88/progranulin; Immunohistochemistry; Non–small cell carcinoma; Prognostic factor; Serum GP88; Serum progranulin.

Conflict of interest statement

Conflicts of Interest

G Serrero, B Yue, D Hicks are full-time employees of A&G Pharmaceutical, Inc. M Edelman, J Feliciano, P Bejarano, O Ioffe, D Reisman, D Hawkins and Q Gai : no conflict of interest concerning the data contained in, or preparation of this manuscript.

Copyright © 2014 Elsevier Inc. All rights reserved.

Figures

Figure 1. Immunohistochemical staining for GP88 expression in paraffin-embedded local NSCLC tissue sections

Representative photomicrographs (magnification x200) of lung cancer tissue sections from local resected NSCLC showing various levels of GP88 expression with 0, 1+, 2+, and 3+ scores, respectively are provided.

Figure 2. Kaplan-Meier estimates for Disease-free survival and Overall survival by GP88 scores for patients with localized NSCLC

GP88 expression for the 85 NSCLC cases was examined by IHC and reported as GP88 scores of 0, 1+, 2+ or 3+. Kaplan-Meier estimates for DFS (a) and OS (c) were determined for each GP88 score group. The difference between the curves was estimated by the log-rank test and were p= 0.0049 for DFS and p= 0.0027 for OS, respectively. Kaplan-Meier estimates for DFS (b) and OS (d) were determined for GP88 staining scores grouped as 3+ and

Figure 2. Kaplan-Meier estimates for Disease-free survival and Overall survival by GP88 scores for patients with localized NSCLC

GP88 expression for the 85 NSCLC cases was examined by IHC and reported as GP88 scores of 0, 1+, 2+ or 3+. Kaplan-Meier estimates for DFS (a) and OS (c) were determined for each GP88 score group. The difference between the curves was estimated by the log-rank test and were p= 0.0049 for DFS and p= 0.0027 for OS, respectively. Kaplan-Meier estimates for DFS (b) and OS (d) were determined for GP88 staining scores grouped as 3+ and

Figure 3. Kaplan-Meier estimates for progression-free survival and overall survival by GP88 scores for patients with localized advanced (Stage III) NSCLC

a: Kaplan-Meier estimates for progression-free survival for each GP88 score (0, 1+, 2+ 3+); b: Kaplan-Meier estimates for progression-free survival for GP88 scores grouped as

Figure 3. Kaplan-Meier estimates for progression-free survival and overall survival by GP88 scores for patients with localized advanced (Stage III) NSCLC

a: Kaplan-Meier estimates for progression-free survival for each GP88 score (0, 1+, 2+ 3+); b: Kaplan-Meier estimates for progression-free survival for GP88 scores grouped as

Figure 4. Comparison of Serum GP88 levels in Stage IIIb/IV NSCLC and non-lung cancer control subjects

Serum was collected from Stage IIIb/IV NSCLC (n=19) and control subjects that did not have lung cancer (n=20). Serum GP88 levels was determined by sandwich EIA as described in the method section.