Abnormalities of the TITF-1 Lineage-Specific Oncogene in NSCLC: Implications in Lung Cancer Pathogenesis and Prognosis

Abstract

Emerging evidence suggests that aberrant expression of oncogenes contributes to development of lung malignancy. The thyroid transcription factor 1 (TITF-1) gene functions as a lineage survival gene abnormally expressed in a significant fraction of non-small cell lung cancers (NSCLC), in particular lung adenocarcinomas. To better characterize TITF-1 abnormality patterns in NSCLC, we studied TITF-1's gene copy number using FISH and quantitative PCR, as well as its protein expression by immunohistochemistry analysis in a tissue microarray comprising surgically resected NSCLC (N = 321) including 204 adenocarcinomas and 117 squamous cell carcinomas (SCC). TITF-1 copy number and protein expression were correlated with patients' clinicopathologic characteristics, and in a subset of adenocarcinomas with EGFR and KRAS mutation status. We found that increased TITF-1 protein expression was prevalent in lung adenocarcinomas only and was significantly associated with female gender (P < 0.001), never-smokers (P = 0.004), presence of EGFR mutations (P = 0.05), and better overall survival (all stages, P = 0.0478; stages I and II, P = 0.002). TITF-1 copy number gain(CNG) was detected by FISH analysis in both adenocarcinomas (18.9%; high CNG, 8.3%) and SCCs (20.1%; high CNG, 3.0%), and correlated significantly with the protein product (P = 0.004) and presence of KRAS mutations (P = 0.008) in lung adenocarcinomas. Moreover, multivariate analysis revealed that TITF-1 copy number gain was an independent predictor of poor survival of NSCLC (P = 0.039). Our integrative study demonstrates that the protein versus genomic patterns of TITF-1 have opposing roles in lung cancer prognosis and may occur preferentially in different subsets of NSCLC patients with distinct oncogene mutations.