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

Research output: Contribution to journalArticle

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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

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Oncogenes
Non-Small Cell Lung Carcinoma
Lung Neoplasms
Mutation
Adenocarcinoma
Proteins
Survival
Gene Dosage
thyroid nuclear factor 1
Thyroid Neoplasms
Genes
Squamous Cell Carcinoma
Research Design
Multivariate Analysis
Immunohistochemistry
Polymerase Chain Reaction
Lung
Adenocarcinoma of lung
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Abnormalities of the TITF-1 lineage-specific oncogene in NSCLC : Implications in lung cancer pathogenesis and prognosis. / Tang, Ximing; Kadara, Humam; Behrens, Carmen; Liu, Diane D.; Xiao, Yun; Rice, David; Gazdar, Adi F.; Fujimoto, Junya; Moran, Cesar; Varella-Garcia, Marileila; Lee, J. Jack; Hong, Waun Ki; Wistuba, Ignacio I.

In: Clinical Cancer Research, Vol. 17, No. 8, 15.04.2011, p. 2434-2443.

Research output: Contribution to journalArticle

Tang, X, Kadara, H, Behrens, C, Liu, DD, Xiao, Y, Rice, D, Gazdar, AF, Fujimoto, J, Moran, C, Varella-Garcia, M, Lee, JJ, Hong, WK & Wistuba, II 2011, 'Abnormalities of the TITF-1 lineage-specific oncogene in NSCLC: Implications in lung cancer pathogenesis and prognosis', Clinical Cancer Research, vol. 17, no. 8, pp. 2434-2443. https://doi.org/10.1158/1078-0432.CCR-10-1412
Tang, Ximing ; Kadara, Humam ; Behrens, Carmen ; Liu, Diane D. ; Xiao, Yun ; Rice, David ; Gazdar, Adi F. ; Fujimoto, Junya ; Moran, Cesar ; Varella-Garcia, Marileila ; Lee, J. Jack ; Hong, Waun Ki ; Wistuba, Ignacio I. / Abnormalities of the TITF-1 lineage-specific oncogene in NSCLC : Implications in lung cancer pathogenesis and prognosis. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 8. pp. 2434-2443.
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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.",
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AU - Tang, Ximing

AU - Kadara, Humam

AU - Behrens, Carmen

AU - Liu, Diane D.

AU - Xiao, Yun

AU - Rice, David

AU - Gazdar, Adi F.

AU - Fujimoto, Junya

AU - Moran, Cesar

AU - Varella-Garcia, Marileila

AU - Lee, J. Jack

AU - Hong, Waun Ki

AU - Wistuba, Ignacio I.

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