P1.05-011 Comparative Analysis of TTF-1 Copy Number Alterations and Protein Expression in Patients with Non-Small Cell Lung Cancer

Abstract

TTF-1 (also known as NKX2-1) is located at chromosome 14q13.3. TTF-1 is a master regulator for the development of normal lung, and is also both a lineage oncogene and a suppressor gene in non-small cell lung cancer (NSCLC). TTF-1 expression is associated with a favorable prognosis. In contrast, the clinical significance of increased TTF-1 gene dosage has yet to be fully elucidated. We explored the relationship of TTF-1 copy number alterations with TTF-1 protein expression as well as patients’ prognoses in a relatively large cohort. We assessed TTF-1 gene copy number and protein expression in micro arrayed 636 NSCLC, including 421 adenocarcinomas and 173 squamous cell carcinomas (SCCs), and 42 other histologies, using fluorescent in situ hybridization and immunohistochemistry. TTF-1 copy number alterations were divided into three categories; amplification (TTF-1/CEP14 ≥2), polysomy (TTF-1/CEP14 <2 and TTF-1 signals ≥4 copies per nucleus), and disomy (the others). Their associations with clinical data were retrospectively analyzed. Among the entire cohort, TTF-1 amplification and polysomy were observed in 5.6% (36/636) and 8.3% (53/636), respectively. Tumors with copy number alterations (amplification and polysomy) were detected in 14.5% (61/421) among adenocarcinomas, 9.3% (17/173) among squamous cell carcinomas, and 26.2% (11/42) among other histologies (P = 0.012). TTF-1 expression was almost exclusively observed in adenocarcinomas (P < 0.001). In the adenocarcinoma cohort, the frequency was 6.7% (28/421) for TTF-1 amplification and 7.8% (33/421) for polysomy. TTF-1 positivity was 84.8% (357/421). A multivariate Cox hazards model analysis demonstrated that TTF-1 amplification was an independent worse prognostic factor (hazard ratio (HR), 3.84; 95% confidence interval (CI), 2.18-6.71) for overall survival, but TTF-1 expression was adversely an independent better prognostic factor (HR, 0.49; 95% CI, 0.28-0.85). In the SCC cohort, there were few cases of TTF-1 amplification (1.7%, 3/173), polysomy (8.1%, 14/173), and TTF-1 expression (3.7%, 10/273). Interestingly, any case of adenocarcinoma and SCC with TTF-1 amplification harbored positive TTF-1 expression. Both TTF-1 amplification and TTF-1 expression were more common in adenocarcinoma. However, they had distinct prognostic roles: TTF-1 amplification was an independent poor prognostic factor in adenocarcinoma, whereas TTF-1 expression was a favorable prognostic factor.