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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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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T1 - Abnormalities of the TITF-1 lineage-specific oncogene in NSCLC

T2 - Implications in lung cancer pathogenesis and prognosis

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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N2 - 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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