Abnormalities of the TITF-1 lineage-specific oncogene in NSCLC: Implications in lung cancer pathogenesis and prognosis

Ximing Tang, Humam Kadara, Carmen Behrens, Diane D. Liu, Yun Xiao, David Rice, Adi F. Gazdar, Junya Fujimoto, Cesar Moran, Marileila Varella-Garcia, J. Jack Lee, Waun Ki Hong, Ignacio I. Wistuba

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60 Scopus citations

Abstract

Purpose: 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. Experimental Design: 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. Results: 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). Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)2434-2443
Number of pages10
JournalClinical Cancer Research
Volume17
Issue number8
DOIs
StatePublished - Apr 15 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Tang, X., Kadara, H., Behrens, C., Liu, D. D., Xiao, Y., Rice, D., Gazdar, A. F., Fujimoto, J., Moran, C., Varella-Garcia, M., Lee, J. J., Hong, W. K., & Wistuba, I. I. (2011). Abnormalities of the TITF-1 lineage-specific oncogene in NSCLC: Implications in lung cancer pathogenesis and prognosis. Clinical Cancer Research, 17(8), 2434-2443. https://doi.org/10.1158/1078-0432.CCR-10-1412