TY - JOUR
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.
PY - 2011/4/15
Y1 - 2011/4/15
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.
AB - 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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U2 - 10.1158/1078-0432.CCR-10-1412
DO - 10.1158/1078-0432.CCR-10-1412
M3 - Article
C2 - 21257719
AN - SCOPUS:79954583049
SN - 1078-0432
VL - 17
SP - 2434
EP - 2443
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 8
ER -