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


METHODS
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.
Departmentsof Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Ximing
X
Tang
Humam
H
Kadara
Carmen
C
Behrens
Diane D
DD
Liu
Yun
Y
Xiao
David
D
Rice
Adi F
AF
Gazdar
Junya
J
Fujimoto
Cesar
C
Moran
Marileila
M
Varella-Garcia
J Jack
JJ
Lee
Waun Ki
WK
Hong
Ignacio I
II
Wistuba
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D009857:Oncogenes / Q000235:genetics*; D011379:Prognosis; D037662:Pulmonary Surfactant-Associated Protein A / Q000378:metabolism; D037701:Pulmonary Surfactant-Associated Protein B / Q000378:metabolism; D037721:Pulmonary Surfactant-Associated Protein C / Q000378:metabolism; D012907:Smoking; D000074482:Thyroid Nuclear Factor 1; D046888:Tissue Array Analysis / Q000706:statistics & numerical data; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics
C000614412:NKX2-1 protein, human; D009687:Nuclear Proteins; D037662:Pulmonary Surfactant-Associated Protein A; D037701:Pulmonary Surfactant-Associated Protein B; D037721:Pulmonary Surfactant-Associated Protein C; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D066246:ErbB Receptors; D018631:ras Proteins
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