title: Negative Thyroid Transcription Factor 1 Expression Defines an Unfavorable Subgroup of Lung Adenocarcinomas.
abstract: BACKGROUND
  Thyroid transcription factor 1 (TTF1) is a master regulator of pulmonary differentiation that is downregulated in a subset of lung adenocarcinoma, of which the clinicopathologic characteristics were not fully clarified.
  
  
  METHODS
  One thousand forty-two lung adenocarcinoma patients who underwent surgery were investigated for clinic characteristics, histologic subtyping, and spectrum of well-identified driver mutations. TTF1 expression was correlated with these clinicopathologic factors and survival.
  
  
  RESULTS
  Compared with TTF1 positive (TTF1+) patients, the 133 negative individuals (12.8%, TTF1-) were more likely to be male (p = 0.006) and heavy smokers (p = 0.002) who had larger tumor size (p < 0.001) and more advanced disease stage (p < 0.001). TTF1- presented more in solid and invasive mucinous-predominant carcinomas (both p < 0.001), whereas TTF1+ was identified in 100% patients with adenocarcinoma in situ, minimally invasive and lepidic-predominant adenocarcinomas. The TTF1- tumors harbored the known driver mutations in significantly low frequency compared with TTF1+ adenocarcinomas (57.8% versus 78.1%, p < 0.001), especially in epidermal growth factor receptor (EGFR) mutations (37.6% versus 60.7%, p < 0.001). There was no significant difference in recurrence-free survival between the TTF1- and TTF1+ patients, either for the whole cohort or stratified by pathologic stage, or among the driver mutation-defined subsets. However, recurrence of multiple metastases was more likely to occur in patients with TTF1- adenocarcinomas (88.1% versus 32.4%, p < 0.001). Multivariate analysis revealed that TTF1- independently predicted both poor postrecurrence survival (hazard ratio = 1.664; 95% confidence interval , 1.097-2.524; p = 0.017) and unfavorable overall survival (hazard ratio = 1.553; 95% confidence interval , 1.013-2.381; p = 0.043).
  
  
  CONCLUSIONS
  TTF1- correlated with solid and invasive mucinous subtypes of lung adenocarcinoma and lower frequency of EGFR mutations. It defines a subgroup of lung adenocarcinomas with unfavorable outcomes.
authors.affiliation: *Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; †Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; ‡Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China; and §Section of Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark.
authors.forename: Yiliang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Yunjian
authors.initials: Y
authors.lastname: Pan
authors.forename: Haichuan
authors.initials: H
authors.lastname: Hu
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hang
authors.initials: H
authors.lastname: Li
authors.forename: Lei
authors.initials: L
authors.lastname: Shen
authors.forename: Yongfu
authors.initials: Y
authors.lastname: Yu
authors.forename: Yihua
authors.initials: Y
authors.lastname: Sun
authors.forename: Haiquan
authors.initials: H
authors.lastname: Chen
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C504003:TTF1 protein, human; D014157:Transcription Factors