Aquaporin 1 Is an Independent Marker of Poor Prognosis in Lung Adenocarcinoma

BACKGROUND: Aquaporin 1 (AQP1) overexpression has been shown to be associated with uncontrolled cell replication, invasion, migration, and tumor metastasis. We aimed to evaluate AQP1 expression in lung adenocarcinomas and to examine its association with clinicopathological features and prognostic significance. We also investigated the association between AQP1 overexpression and epithelial-mesenchymal transition (EMT) markers. METHODS: We examined AQP1 expression in 505 cases of surgically resected lung adenocarcinomas acquired at the Seoul National University Bundang Hospital from 2003 to 2012. Expression of AQP1 and EMT-related markers, including Ecadherin and vimentin, were analyzed by immunohistochemistry and tissue microarray. RESULTS: AQP1 overexpression was associated with several aggressive pathological parameters, including venous invasion, lymphatic invasion, and tumor recurrence. AQP1 overexpression tended to be associated with higher histological grade, advanced pathological stage, and anaplastic lymphoma kinase (ALK) translocation; however, these differences were not statistically significant. In addition, AQP1 overexpression positively correlated with loss of E-cadherin expression and acquired expression of vimentin. Lung adenocarcinoma patients with AQP1 overexpression showed shorter progression-free survival (PFS, 46.1 months vs. 56.2 months) compared to patients without AQP1 overexpression. Multivariate analysis confirmed that AQP1 overexpression was significantly associated with shorter PFS (hazard ratio, 1.429; 95% confidence interval, 1.033 to 1.977; p=.031). CONCLUSIONS: AQP1 overexpression was thereby concluded to be an independent factor of poor prognosis associated with shorter PFS in lung adenocarcinoma. These results suggested that AQP1 overexpression might be considered as a prognostic biomarker of lung adenocarcinoma.

Membranous Insulin-like Growth Factor-1 Receptor (IGF1R) Expression Is Predictive of Poor Prognosis in Patients with Epidermal Growth Factor Receptor (EGFR)-Mutant Lung Adenocarcinoma

BACKGROUND: Insulin-like growth factor-1 receptor (IGF1R) is a membrane receptor-type tyrosine kinase that has attracted considerable attention as a potential therapeutic target, although its clinical significance in non-small cell lung cancer (NSCLC) is controversial. This study aimed to clarify the clinical significance of IGF1R expression in human NSCLC. METHODS: IGF1R protein expression was evaluated using immunohistochemistry in 372 patients with NSCLC who underwent curative surgical resection (146 squamous cell carcinomas [SqCCs] and 226 adenocarcinomas [ADCs]). We then analyzed correlations between expression of IGF1R and clinicopathological and molecular features and prognostic significance. RESULTS: Membranous and cytoplasmic IGF1R expression were significantly higher in SqCCs than in ADCs. In patients with SqCC, membranous IGF1R expression was associated with absence of vascular, lymphatic, and perineural invasion; lower stage; and better progression-free survival (PFS) (hazard ratio [HR], 0.586; p = .040). In patients with ADC, IGF1R expression did not have a significant prognostic value; however, in the subgroup of epidermal growth factor receptor (EGFR)-mutant ADC, membranous IGF1R expression was associated with lymphatic and perineural invasion, solid predominant histology, and higher cancer stage and was significantly associated with worse PFS (HR, 2.582; p = .009). CONCLUSIONS: Lung ADC and SqCC showed distinct IGF1R expression profiles that demonstrated prognostic significance. High membranous IGF1R expression was predictive of poor PFS in EGFR-mutant lung ADC, while it was predictive of better PFS in SqCC. These findings will help improve study design for subsequent investigations and select patients for future anti-IGF1R therapy.

Clinicopathologic Implications of ALK Gene Copy Number Gain in Non-small Cell Lung Cancer

PURPOSE: The anaplastic lymphoma kinase (ALK) gene is a potential molecular target in non-small cell lung carcinoma (NSCLC). The clinicopathologic implication of a change in the ALK gene copy number (GCN) is unclear. MATERIALS AND METHODS: A total of 434 primary NSCLC samples were analyzed by fluorescence in situ hybridization (FISH) for ALK GCN. RESULTS: Ninety-six cases (22.1%) showed ALK GCN gain with amplification in 16 (3.7%) cases. The cases with ALK GCN gain consisted of 47 adenocarcinomas (49.0%), 41 squamous cell carcinomas (42.7%), 5 adenosquamous carcinomas (5.2%) and 3 other NSCLCs (3.1%). ALK gene amplification was identified in 7 adenocarcinomas (43.7%) and 9 squamous cell carcinomas (56.3%). There was no significant difference between ALK GCN gain/amplification and histologic subtypes. Univariate survival analysis revealed that patients with ALK GCN gain/amplification showed shorter progression-free survival durations and decreased overall survival rates (p<0.001). However, multivariate analysis proved that ALK GCN gain/amplification is not an independent prognostic factor for progression-free survival or overall survival. CONCLUSION: ALK GCN gain is frequently identified in NSCLCs and the incidence is similar among histologic subtypes. Although ALK GCN gain/amplification is not an independent prognostic marker, it is associated with tumor progression in NSCLC.