title: Distinct prognostic roles and heterogeneity of TTF1 copy number and TTF1 protein expression in non-small cell lung cancer.
abstract: Thyroid transcription factor 1 (TTF1) located on chromosome band 14q13.3 is an oncogene and a suppressor gene in non-small cell lung cancer (NSCLC). The prognostic relevance of TTF1 copy number alterations (CNAs) and their association with TTF1 protein expression are poorly understood. Here, we assessed TTF1 CNAs and protein expression using microarrays in a cohort of 636 NSCLC, including 423 adenocarcinoma (ADC) and 171 squamous cell carcinoma (SCC). In addition, fluorescent in situ hybridization and immunohistochemistry were performed. TTF1 CNAs were detected in 23% of NSCLC (23% of ADC and 20% of SCC). Specifically, TTF1 amplification and polysomy were observed in 5% and 18% of NSCLC, and in 7% and 16% of ADC, respectively. TTF1 expression was detected in 85% of ADC. TTF1 CNAs were significantly associated with advanced tumor stage, EGFR mutations, and TTF1 expression. A multivariate Cox hazards model analysis of overall survival and recurrence-free survival demonstrated that both TTF1 amplification and polysomy were independent indicators of an unfavorable prognosis in patients with NSCLC. Survival was inversely correlated with TTF1 copy number. In contrast, TTF1 protein expression was an independent favorable prognostic factor. Intratumoral and intertumoral heterogeneities of TTF1 CNAs and TTF1 protein expression were assessed using primary cores from 138 pairs of primary tumors and corresponding nodal metastases. The concordance rate for TTF1 CNAs and TTF1 protein expression was high within tumors and between primary and metastatic tumors. Altogether, these results suggest that TTF1 CNAs are correlated with TTF1 protein expression, but have opposing effects on survival.
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.|Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Yoshimura
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.|Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Department of Respiratory Medicine, Shizuoka City Shimizu Hospital, Shizuoka, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Mori
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Iwashita
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Kahyo
authors.affiliation: First Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Akikazu
authors.initials: A
authors.lastname: Kawase
authors.affiliation: Division of Thoracic Surgery, Respiratory Disease Center, Seirei Mikatahara General Hospital, Hamamatsu, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tanahashi
authors.affiliation: Department of Pathology, Seirei Mikatahara General Hospital, Hamamatsu, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ogawa
authors.affiliation: Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.|Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Inui
authors.affiliation: First Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Funai
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shinmura
authors.affiliation: Division of Thoracic Surgery, Respiratory Disease Center, Seirei Mikatahara General Hospital, Hamamatsu, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Niwa
authors.affiliation: Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Suda
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Haruhiko
authors.identifier: 0000-0002-0779-3088
authors.initials: H
authors.lastname: Sugimura
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D014157:Transcription Factors; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C504003:TTF1 protein, human; D014157:Transcription Factors