Gene Summary

Gene:NKX2-1; NK2 homeobox 1
Aliases: BCH, BHC, NK-2, TEBP, TTF1, NKX2A, T/EBP, TITF1, TTF-1, NKX2.1
Summary:This gene encodes a protein initially identified as a thyroid-specific transcription factor. The encoded protein binds to the thyroglobulin promoter and regulates the expression of thyroid-specific genes but has also been shown to regulate the expression of genes involved in morphogenesis. Mutations and deletions in this gene are associated with benign hereditary chorea, choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress, and may be associated with thyroid cancer. Multiple transcript variants encoding different isoforms have been found for this gene. This gene shares the symbol/alias 'TTF1' with another gene, transcription termination factor 1, which plays a role in ribosomal gene transcription. [provided by RefSeq, Feb 2014]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:homeobox protein Nkx-2.1
Source:NCBIAccessed: 17 March, 2015


What does this gene/protein do?
Show (47)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 March 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Genetic Predisposition
  • Transcriptome
  • Nuclear Proteins
  • Molecular Sequence Data
  • Oncogenes
  • Cancer Gene Expression Regulation
  • Papillary Carcinoma
  • Cell Differentiation
  • Thyroid Cancer
  • MicroRNAs
  • Epidermal Growth Factor Receptor
  • Genome, Human
  • Single Nucleotide Polymorphism
  • Case-Control Studies
  • Gene Expression Profiling
  • Gene Amplification
  • Down-Regulation
  • Tumor Markers
  • Neoplasms, Experimental
  • Adenocarcinoma
  • Forkhead Transcription Factors
  • Neoplastic Cell Transformation
  • Cell Proliferation
  • thyroid nuclear factor 1
  • Messenger RNA
  • Squamous Cell Carcinoma
  • Oligonucleotide Array Sequence Analysis
  • Genetic Association Studies
  • Chromosome 14
  • Homeodomain Proteins
  • Genome-Wide Association Study
  • Adolescents
  • Base Sequence
  • Lung
  • Transcription Factors
  • Childhood Cancer
  • Non-Small Cell Lung Cancer
  • Lung Cancer
  • Signal Transduction
  • Genotype
  • Staging
Tag cloud generated 17 March, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NKX2-1 (cancer-related)

Shiau CJ, Babwah JP, da Cunha Santos G, et al.
Sample features associated with success rates in population-based EGFR mutation testing.
J Thorac Oncol. 2014; 9(7):947-56 [PubMed] Related Publications
INTRODUCTION: Epidermal growth factor receptor (EGFR) mutation testing has become critical in the treatment of patients with advanced non-small-cell lung cancer. This study involves a large cohort and epidemiologically unselected series of EGFR mutation testing for patients with nonsquamous non-small-cell lung cancer in a North American population to determine sample-related factors that influence success in clinical EGFR testing.
METHODS: Data from consecutive cases of Canadian province-wide testing at a centralized diagnostic laboratory for a 24-month period were reviewed. Samples were tested for exon-19 deletion and exon-21 L858R mutations using a validated polymerase chain reaction method with 1% to 5% detection sensitivity.
RESULTS: From 2651 samples submitted, 2404 samples were tested with 2293 samples eligible for analysis (1780 histology and 513 cytology specimens). The overall test-failure rate was 5.4% with overall mutation rate of 20.6%. No significant differences in the failure rate, mutation rate, or mutation type were found between histology and cytology samples. Although tumor cellularity was significantly associated with test-success or mutation rates in histology and cytology specimens, respectively, mutations could be detected in all specimen types. Significant rates of EGFR mutation were detected in cases with thyroid transcription factor (TTF)-1-negative immunohistochemistry (6.7%) and mucinous component (9.0%).
CONCLUSIONS: EGFR mutation testing should be attempted in any specimen, whether histologic or cytologic. Samples should not be excluded from testing based on TTF-1 status or histologic features. Pathologists should report the amount of available tumor for testing. However, suboptimal samples with a negative EGFR mutation result should be considered for repeat testing with an alternate sample.

Varinot J, Ménégaux F, Bitker MO, Compérat E
Renal metastasis from thyroid carcinoma: a case report.
Anal Quant Cytopathol Histpathol. 2014; 36(1):46-50 [PubMed] Related Publications
BACKGROUND: Renal metastases of thyroid carcinomas occur rarely and represent about 3% of all metastases to the kidney, with only 23 single case study reports in the English language literature.
CASE: A 77-year-old man presented with gross hematuria. CT scan showed a posterior and cortico-sinusal mass in the right kidney measuring 5 x 3 cm. On gross examination the kidney was occupied by a lobulated mass measuring 4.5 cm in its greatest dimension. Microscopically, there was a papillary and follicular proliferation with colloid-like materials in the intrafollicular space. The strong positive immunohistochemical stain of thyroglobulin and thyroid transcription factor-1 confirmed the origin of thyroid gland and the diagnosis of renal metastasis of thyroid carcinoma.
CONCLUSION: Although rare, the renal metastasis of a thyroid carcinoma is a diagnostic to consider even if the renal mass is unilateral and the patient has no history of thyroid surgery. The main differential diagnostic is the primitive thyroid-like follicular carcinoma of the kidney. Immunohistochemistry often leads to the right diagnosis, which is crucial for the management of the patient. Renal metastases of thyroid carcinomas are rare and often present as a primitive unilateral renal mass.

Matsukuma S, Obara K, Kato K, et al.
Non-sarcomatous spindle cell morphology in conventional lung adenocarcinoma: a clinicopathological study.
Virchows Arch. 2014; 465(2):165-72 [PubMed] Related Publications
Non-sarcomatous spindle cell foci (N-SSCF) without aggressive invasiveness, also called morule-like lesions, occur occasionally in conventional lung adenocarcinoma, but their characteristics remain poorly understood. We identified N-SSCF in 7 (4.0 %) of 173 lung adenocarcinomas and examined their clinicopathological features. The patients were six men and one woman with a mean age of 57.0 years (range, 43-76 years). All tumors were papillary-predominant adenocarcinomas, ranging in size from 1 to 4.5 cm (mean, 2.7 cm). N-SSCF occupied 10-30 % of the tumors, and in all cases, there were focal or multifocal transitions between the two morphotypes. Most N-SSCF were plug-like nodules filling the spaces of cancerous alveoli/tubules or patchy insular nests. N-SSCF frequently contained mucin + lumina and were positive for cytokeratin 7, thyroid transcription factor 1, and Napsin A, but negative for cytokeratin 5/6 and vimentin, similar to the adenocarcinoma cells of the same tumor. Five cases (71 %) were at stage I or II, suggesting that N-SSCF can occur in an early phase of lung cancer. In an age-, sex-, and stage-matched control study, N-SSCF were not associated with prognosis (P = 0.471). We consider tumors with N-SSCF a distinct structural variant of adenocarcinoma without prognostic significance. They should be distinguished from true sarcomatous spindle cells and micropapillary components, which are associated with aggressive behavior.

Alderton GK
Metastasis: shedding is no easy task.
Nat Rev Cancer. 2014; 14(6):383 [PubMed] Related Publications

Kujawa A, Olias P, Böttcher A, Klopfleisch R
Thyroid transcription factor-1 is a specific marker of benign but not malignant feline lung tumours.
J Comp Pathol. 2014; 151(1):19-24 [PubMed] Related Publications
Feline lung tumours are currently subclassified according to the criteria of the World Health Organisation, but this scheme contains overlap in the tumour phenotype. The aims of the present study were to re-evaluate the histological features of feline lung tumours and to correlate these with expression of the markers thyroid transcription factor (TTF)-1 and Ki67. TTF-1 was found to be a highly specific marker for neoplastic and non-neoplastic lung tissue and thyroid tissue, but was expressed only weakly in invasive lung tumours. A combined semiquantitative score for Ki67 and TTF-1 expression correlated well with differentiation and invasive behaviour of the tumours and may thus be of potential value for evaluation of feline lung tumours.

Caswell DR, Chuang CH, Yang D, et al.
Obligate progression precedes lung adenocarcinoma dissemination.
Cancer Discov. 2014; 4(7):781-9 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Despite its clinical importance, very little is known about the natural history and molecular underpinnings of lung cancer dissemination and metastasis. Here, we used a genetically engineered mouse model of metastatic lung adenocarcinoma in which cancer cells are fluorescently marked to determine whether dissemination is an inherent ability or a major acquired phenotype during lung adenocarcinoma metastasis. We find very little evidence for dissemination from oncogenic KRAS-driven hyperplasias or most adenocarcinomas. p53 loss is insufficient to drive dissemination but rather enables rare cancer cells in a small fraction of primary adenocarcinomas to gain alterations that drive dissemination. Molecular characterization of disseminated tumor cells indicates that downregulation of the transcription factor Nkx2-1 precedes dissemination. Finally, we show that metastatic primary tumors possess a highly proliferative subpopulation of cells with characteristics matching those of disseminating cells. We propose that dissemination is a major hurdle during the natural course of lung adenocarcinoma metastasis.
SIGNIFICANCE: Because of its aggressively metastatic nature, lung cancer is the top cancer killer of both men and women in the United States. We show that, unlike in other cancer types, lung cancer dissemination is a major initial barrier to metastasis. Our findings provide insight into the effect of p53 deficiency and downregulation of Nkx2-1 during lung adenocarcinoma progression.

Caliò A, Nottegar A, Gilioli E, et al.
ALK/EML4 fusion gene may be found in pure squamous carcinoma of the lung.
J Thorac Oncol. 2014; 9(5):729-32 [PubMed] Related Publications
INTRODUCTION: The report of cases of lung squamous cell cancers harboring anaplastic lymphoma kinase (ALK) gene rearrangements raises the question whether this histologic subtype should be also evaluated for such molecular predictive test.
METHODS: A consecutive series of 40 lung pure squamous cell carcinomas were analyzed for ALK gene status by fluorescence in situ hybridization. Squamous differentiation was validated using an immunohistochemical panel including n-p63 (p40), cytokeratin (CK) 5/6, sex-determining region Y (SRY)-Box2 (SOX2), thyroid transcription factor 1, CK7, and Napsin-A.
RESULTS: Squamous differentiation was confirmed in all tumors as they stained positive for n-p63 and CK5/6 and negative for thyroid transcription factor 1 and Napsin-A. One of 40 cases (2.5%) showed an ALK rearrangement on fluorescence in situ hybridization analysis.
CONCLUSIONS: ALK translocation may be found in lung pure squamous cell carcinomas. Our data suggest the opportunity to test ALK rearrangements on biopsy samples harboring squamous cell cancer differentiation.

An J, Park S, Sung SH, et al.
Unusual expression of thyroid transcription factor 1 and napsin A in metastatic adenoid cystic carcinoma of extrapulmonary origin in the lung.
Am J Clin Pathol. 2014; 141(5):712-7 [PubMed] Related Publications
OBJECTIVES: Our study examines thyroid transcription factor 1 (TTF-1) expression in 40 primary adenoid cystic carcinomas (ACCs) arising in various sites and compares TTF-1 expression between primary and metastatic ACCs in 12 cases with distant metastases.
METHODS: Forty patients with ACCs, including 12 pairs of primary and metastatic ACCs, were evaluated for the immunohistochemical expression of TTF-1 (clone SPT24). In addition, 10 metastatic ACCs to the lung were tested on napsin A and a different TTF-1 antibody (clone 8G7G3) for further evaluation.
RESULTS: No primary ACCs showed TTF-1 immunoreactivity (clone SPT24). TTF-1 was positive in five (41.7%) of 12 metastatic ACCs; all five cases were found only in the lung and comprised five (50.0%) of 10 cases. In all positive cases, staining was focal and detected only in the cribriform histologic subtype. Staining patterns using both antibodies (both SPT24 and 8G7G3) were very similar, and TTF-1-positive tumor cells were also positive for napsin A. Extrapulmonary ACCs were all negative for TTF-1 regardless of origination and metastasis.
CONCLUSIONS: TTF-1- and napsin A-positive ACCs in the lung should not be considered primary ACCs because TTF-1 and napsin A can be expressed in metastatic ACCs of the lung.

Fallet V, Cadranel J, Doubre H, et al.
Prospective screening for ALK: clinical features and outcome according to ALK status.
Eur J Cancer. 2014; 50(7):1239-46 [PubMed] Related Publications
The aim of this study was to analyse the clinico-pathological characteristics and outcomes of a cohort of French patients who were prospectively screened for Anaplastic Lymphoma Kinase (ALK) rearrangement. One hundred and sixteen consecutive patients screened for ALK rearrangement to be recruited into a crizotinib registration trial were included from eight French centres. ALK rearrangement was detected by fluorescence in situ hybridization. Seventeen patients (14.6%) were positive for ALK. ALK+ patients were younger (p = 0.049) and more likely to be males (p=0.032), non- or light-smokers (p = 0.048) and without underlying respiratory disease (p=0.025) compared to ALK- patients. Thyroid-transcription factor-1 expression was present in all ALK+ tumours. ALK+ tumours tended to have lymph node and brain metastases. In multivariate analyses, gender, smoking history and N stage were independently associated with ALK status. Median overall survival (OS) was not reached for ALK+ patients and was significantly longer than for ALK- patients (hazard ratio for death for ALK- patients 2.98; 95% CI [1.29-6.90], p=0.01). French ALK+ patients present a specific phenotype. ALK rearrangement should be determined to improve OS with an effective targeted therapy.

Zhu B, Dalal S, Kamp DW, Lin X
Warranting investigation of primary lung adenocarcinoma in patients with an extrapulmonary malignancy and lung nodules due to high frequency.
Am J Clin Pathol. 2014; 141(3):429-36 [PubMed] Related Publications
OBJECTIVES: To distinguish primary lung adenocarcinoma (PLA) from metastatic adenocarcinoma/malignancy to optimize therapy.
METHODS: We investigated the utility of thyroid transcription factor 1 (TTF-1) and napsin A in distinguishing PLA from metastatic adenocarcinoma/malignancy and assessed the frequency of PLA in patients with extrapulmonary malignancy/adenocarcinoma (PLA-EPM/EPA).
RESULTS: TTF-1 and napsin A identified PLA in PLA-EPM/ EPA with a sensitivity of 89.4% and 93.3% and a specificity of 93.9% and 94.7%, respectively. PLA was confirmedin 47.4% of PLA-EPM and 40.2% of PLA-EPA. Overall, 38.5% of patients with PLA had EPM. The common organs for PLA-EPA were breast (35.8%), colon (13.2%), and others, whereas the common organs resulting in pulmonary metastasis were the colon (32.8%), breast (28.1%), and others. A patient with a smoking history and without EPM had a higher chance of having PLA. Multiple nodules are not a reliable indication of metastatic adenocarcinoma.
CONCLUSIONS: Our results firmly support the role of TTF-1 and napsin A in identifying PLA-EPM/EPA. We reason that all new lung nodules in patients with a history of EPM should be screened using these techniques due to the high frequency of PLA-EPM, which will affect treatment and prognosis of patients with EPM/EPA.

Ai L, Yu Y, Liu X, et al.
Are the SNPs of NKX2-1 associated with papillary thyroid carcinoma in the Han population of Northern China?
Front Med. 2014; 8(1):113-7 [PubMed] Related Publications
Papillary thyroid carcinoma (PTC) is one of the most common tumors of the thyroid gland. The common risk factors of PTC include ionizing radiation, positive family history, and thyroid nodular disease. PTC was identified in Europeans by conducting a genome-wide association study, and a strong association signal with PTC was observed in rs944289 and NKX2-1 (located at the 14q13.3 locus), which was probably the genetic risk factor of PTC. This study aimed to examine the association of this gene with PTC in Chinese. A total of 354 patients with PTC and 360 healthy control subjects from the Han population of Northern China were recruited in the study. These individuals were genotyped to determine rs12589672, rs12894724, rs2076751, and rs944289. The association of rs944289 with PTC was obtained (C vs. T, P = 0.027, OR = 1.264, 95% CI = 1.026 - 1.557; and C/C - C/T vs. T/T, P = 0.034, OR = 1.474, 95% CI = 1.028 - 2.112). Conducting a subgroup analysis, we found a marginal difference in the allele frequency distribution of rs944289 (adjusted P = 0.062) between the patients with PTC and multi-nodular goiter and the control subjects. We also observed an interaction (P = 0.029; OR = 2.578, 95% CI = 1.104 - 6.023) between rs944289 and diabetes in patients with PTC. In conclusion, rs944289 was associated with an increased risk of PTC in the Han population of Northern China, but no clear association was observed in either of the tag single nucleotide polymorphisms of NKX2-1.

Gao Q, Piao YS, Lu DH, et al.
[Secretory adenocarcinoma of lung with brain metastasis: report of a case].
Zhonghua Bing Li Xue Za Zhi. 2013; 42(10):695-6 [PubMed] Related Publications

Surrey LF, Frank R, Zhang PJ, Furth EE
TTF-1 and Napsin-A are expressed in a subset of cholangiocarcinomas arising from the gallbladder and hepatic ducts: continued caveats for utilization of immunohistochemistry panels.
Am J Surg Pathol. 2014; 38(2):224-7 [PubMed] Related Publications
Thyroid transcription factor-1 (TTF-1) and Napsin-A (NapA) are frequently used to classify a tumor of unknown origin as lung or thyroid primary. Although recent studies have shown that nuclear TTF-1 positivity occasionally occurs in adenocarcinoma of nonpulmonary or thyroid origin dependent upon the antibody clone, TTF-1 has been reported as negative or infrequently positive in tumors of biliary origin. On the basis of an index case of cholangiocarcinoma expressing TTF-1, we were prompted to study TTF-1 and NapA positivity in cholangiocarcinoma. Archived paraffin-embedded tissue blocks from liver, gallbladder, and pancreato-biliary resections were chosen for cholangiocarcinoma (n=33) and non-neoplastic intrahepatic and extrahepatic biliary epithelium control tissue (n=26). Immunohistochemical analysis for TTF-1 and NapA was performed and graded for intensity and quantity. TTF-1 was negative in control biliary tissue but positive in 27.2% of cholangiocarcinomas. All TTF-1-positive cases (n=9) were extrahepatic (P=0.01), and most arose from the upper biliary tract (gallbladder and hepatic ducts). TTF-1 positivity was associated with age 60 years and above (P=0.01) but not with sex. Three TTF-1-positive cases were also NapA positive. NapA staining showed apical granular staining of the adjacent non-neoplastic epithelium in 6 cases (18.1%). In summary, 47.4% of extrahepatic cholangiocarcinoma expressed TTF-1, 33.3% of which coexpressed NapA. Cholangiocarcinoma should be considered in the differential when evaluating a TTF-1-positive tumor of unknown primary. As TTF-1 and NapA are not known for biliary system development or detected in non-neoplastic biliary epithelium, the significance of this "pulmonary" phenotype in a subset of extrahepatic cholangiocarcinoma is unknown and needs further investigation.

Jie-Liu, Li XY, Zhao YQ, et al.
Genotype-phenotype correlation in Chinese patients with pulmonary mixed type adenocarcinoma: Relationship between histologic subtypes, TITF-1/SP-A expressions and EGFR mutations.
Pathol Res Pract. 2014; 210(3):176-81 [PubMed] Related Publications
This study aimed to explore the association between adenocarcinoma-related morphological and molecular characteristics and EGFR mutations in Chinese lung adenocarcinomas. A total of 139 consecutively resected pulmonary adenocarcinoma patients were screened for EGFR mutations by the amplification refractory mutation system assay. For the resected specimens, histologic subtypes were sub-classified using either the 2004 WHO classification or the 2011 IASLC/ATS/ERS classification. Meanwhile, TITF-1 (thyroid transcription factor 1) and SP-A (surfactant-associated protein A) immunohistochemistry staining was also detected. The results were correlated with EGFR mutations and clinicopathological features mentioned above. Both sub-classification methods reflected differences in frequencies of EGFR mutations in lung adenocarcinoma subtypes. In summary, mixed non-mucinous bronchioloalveolar carcinoma (BAC) or papillary components and papillary predominant adenocarcinoma showed a higher frequency of EGFR mutations than mucinous BAC components; Also, EGFR mutations were significantly more common in tumors with TITF-1 or SP-A expressions than in those without (p=0.002, p=0.026), especially the sensitivity of TITF-1 (96.9%) and the negative predictive value of TITF-1 (88.2%). Our data further showed significant genotype-phenotype correlations between EGFR mutations and adenocarcinoma-related morphological and molecular characteristics, and patients with special histologic and IHC staining features might have higher EGFR mutation rates. In addition, this study, for the first time, indicated the significant relationship between SPA IHC and EGFR mutations, which needed confirmation by further research.

Selivanova LS, Tertychnyĭ AS
[Sclerosing mucoepidermoid carcinoma with eosinophilia of the thyroid gland].
Arkh Patol. 2013 Sep-Oct; 75(5):44-9 [PubMed] Related Publications
The paper characterizes sclerosing mucoepidermoid carcinoma with eosinophilia, a rare thyroid tumor, including histological and immunohistochemical features. The authors give their observation of a 26-year-old patient. The immunohistochemical findings (positive p63 and TTF-1 tumor cell nuclear staining) show the dual nature of a tumor arising from the cells of the ultimobranchial body and follicular epithelium.

Terra SB, Aubry MC, Yi ES, Boland JM
Immunohistochemical study of 36 cases of pulmonary sarcomatoid carcinoma--sensitivity of TTF-1 is superior to napsin.
Hum Pathol. 2014; 45(2):294-302 [PubMed] Related Publications
Immunohistochemistry is often used to distinguish pulmonary sarcomatoid carcinoma from morphologic mimics. Napsin-A is a pulmonary adenocarcinoma marker, but literature on expression in sarcomatoid carcinoma is limited. Thirty-six cases of sarcomatoid carcinoma were stained for napsin, TTF-1, Oscar, CAM5.2, AE1/AE3, desmin, SMA, S-100, CK5/6, calretinin, D2-40, and WT1. Patients were 24 men and 12 women (mean, 70 years; range, 46-93). There were 27 pleomorphic carcinomas, 5 spindle cell carcinomas, 3 carcinosarcomas, and 1 giant cell carcinoma. Cases were positive for at least 1 keratin: AE1/3 was positive in all 36 cases; Oscar, in 34 cases (94%); and CAM5.2, in 32 cases (89%, weaker/more focal). Napsin was positive in 14 cases (39%): 8 diffuse, 3 focal, and 3 rare cells. TTF-1 was positive in 22 cases (61%): 15 diffuse, 3 focal, and 4 rare cells. No cases were napsin positive and negative for TTF-1. Variable staining for mesothelial markers was observed, including positivity for calretinin (12 cases, 33%), WT1 (6 cases, 17%), D2-40 (5 cases, 14%), and CK5/6 (9 cases, 25%). Mesenchymal markers were also sometimes positive (usually focal), including S-100 (4 cases, 11%), desmin (4 cases, 11%), and SMA (7 cases, 19%, 1 diffuse). In conclusion, TTF-1 is more sensitive than napsin for detection of sarcomatoid carcinoma, and no cases were positive for napsin but negative for TTF-1. CAM5.2 is less sensitive than AE1/AE3 and Oscar. Use of a thoughtful immunohistochemical panel is important in the evaluation of sarcomatoid carcinoma because mesothelial and mesenchymal markers can be expressed.

Ervine A, Leung S, Gilks CB, McCluggage WG
Thyroid transcription factor-1 (TTF-1) immunoreactivity is an adverse prognostic factor in endometrioid adenocarcinoma of the uterine corpus.
Histopathology. 2014; 64(6):840-6 [PubMed] Related Publications
AIMS: It is known that thyroid transcription factor-1 (TTF-1) is expressed in a small percentage of primary gynaecological adenocarcinomas. Following the observation of TTF-1 positivity in a number of endometrioid adenocarcinomas of the uterine corpus which behaved aggressively, we undertook immunohistochemical staining of a large series of endometrial adenocarcinomas of various types to investigate whether its expression is of prognostic significance.
METHODS AND RESULTS: TTF-1 was performed on tissue microarrays containing 102 low-grade (grades 1 or 2) endometrioid adenocarcinomas, 101 grade 3 endometrioid adenocarcinomas, 89 serous adenocarcinomas and 29 clear cell carcinomas. All categories of endometrial adenocarcinoma exhibited TTF-1 staining in a small subset of cases (2% low-grade endometrioid, 11% grade 3 endometrioid, 9% serous, 7% clear cell). TTF-1 was less frequently expressed in low-grade endometrioid adenocarcinomas compared to other subtypes. Endometrioid adenocarcinomas which expressed TTF-1 had a statistically significant worse prognosis with poorer disease-specific survival, and this was also statistically significant in the group of low-grade endometrioid adenocarcinomas.
CONCLUSIONS: Our study confirms that TTF-1 is expressed in a small, but not insignificant, proportion of endometrial adenocarcinomas. TTF-1 positivity in low-grade endometrioid adenocarcinomas is an indicator of poorer prognosis.

He DM, Hou YY
[Practical value of thyroid transcription factor-1 expression by immunohistochemistry in pathologic diagnosis of tumors].
Zhonghua Bing Li Xue Za Zhi. 2013; 42(8):566-9 [PubMed] Related Publications

Sinna EA, Ezzat N, Sherif GM
Role of thyroid transcription factor-1 and P63 immunocytochemistry in cytologic typing of non-small cell lung carcinomas.
J Egypt Natl Canc Inst. 2013; 25(4):209-18 [PubMed] Related Publications
PURPOSE: Evaluation of the value of thyroid transcription factor (TTF-1) and P63 in subtyping of non-small cell lung cancer in cytologic material.
PATIENTS AND METHODS: This is a retrospective study including 40 cases of primary lung lesions who underwent image guided FNAC from pulmonary nodules. The final histopathologic diagnosis was the gold standard. Cell blocks were stained with anti-TTF-1, and P63. Nuclear immunoreactivity for both markers was considered specific. Sensitivity, specificity, positive and negative predictive values, of the cytologic diagnosis and of the two markers, as well as the accuracy of the combined markers were calculated.
RESULTS: Cytomorphology achieved a sensitivity of 83.3%, specificity of 91%, PPV of 91%, and NPV of 83.3%, for the diagnosis of AC, and 91% sensitivity, 83.3% specificity, 83.3% PPV, and 91% NPV, for the diagnosis of SCC. The concordance between cytologic and histopathologic diagnoses of AC and SCC was 87%. TTF-1 achieved 87.5% sensitivity, 94.7% specificity, 95.5% PPV, and 85.7% NPV for AC, while P63 achieved 94.7% sensitivity, 95.8% specificity, 94.7% PPV, and 95.8% NPV for SCC. TTF-1 enhanced the sensitivity of cytomorphology for AC from 83.3% to 87.5%, and specificity from 91% to 94.7%. Similarly P63 enhanced the sensitivity for SCC from 91% to 94.7%, and specificity from 83.3% to 95.8%.
CONCLUSION: TTF-1 achieved moderate sensitivity, and high specificity in the diagnosis of AC, while P63 was highly sensitive and specific for the diagnosis of SCC. Immunocytochemistry raised the sensitivity and specificity of FNAC in diagnosing AC and SCC using TTF-1 and P63, respectively.

Casavant BP, Strotman LN, Tokar JJ, et al.
Paired diagnostic and pharmacodynamic analysis of rare non-small cell lung cancer cells enabled by the VerIFAST platform.
Lab Chip. 2014; 14(1):99-105 [PubMed] Free Access to Full Article Related Publications
Lung cancer is the leading cause of cancer-related deaths in the United States and worldwide. This has led to major research initiatives focusing on improving early diagnosis rate, as well as the development of pharmacodynamic biomarkers. However, broad clinical integration of these approaches is limited due to the invasive nature of lung biopsies, needle aspirates and resections. Recently, an advance for sampling suspicious lung nodules to collect mini-bronchoalveolar lavage (mBAL) samples was shown to be diagnostically relevant but limited by standard cytology techniques leading to low sensitivity and specificity. In addition, a second non-invasive method that holds great promise is the collection of circulating tumor cells, a rare population of tumor cells that have shed into peripheral circulation from primary or metastatic tumor sites, from blood. Here, we utilize a recently published platform, VerIFAST, for the capture and proteomic analysis of rare cells, to isolate cells of interest from lung cancer patients using both mBAL and blood samples. The VerIFAST platform leverages surface tension at the microscale to pin aqueous and oil fluids in adjacent chambers to create a virtual filter between two aqueous fluids. In this manuscript, the VerIFAST was further enhanced to include oil pinning, which allowed on-device tumbling, further eliminating a laborious and time consuming step that could result in increased sample loss. Finally, we further developed the base assays used in standard histopathologic assays for diagnostic and pharmacodynamic analysis of these rare lung cancer cells. Specifically, we examined thyroid transcription factor-1 (TTF-1) signal intensity, in which loss is associated with more aggressive disease, and epidermal growth factor receptor (EGFR) signal intensity, which is a high value therapeutic target in lung cancer.

Ni YB, Tsang JY, Shao MM, et al.
TTF-1 expression in breast carcinoma: an unusual but real phenomenon.
Histopathology. 2014; 64(4):504-11 [PubMed] Related Publications
AIMS: To evaluate thyroid transcription factor-1 (TTF-1) expression in a large cohort of invasive breast carcinomas (IBCs) using two commercially available monoclonal antibody clones (8G7G3/1 and SPT24).
METHODS AND RESULTS: Nuclear and cytoplasmic TTF-1 expression was evaluated in 1132 primary IBCs and 208 primary pulmonary carcinomas using tissue microarray (TMA) sections. TTF-1 nuclear expression was detected in one of 1132 (0.09%) IBCs by 8G7G3/1. In pulmonary carcinoma, TTF-1 expression was detected in 149 (71.6%) and 147 (70.6%) cases by 8G7G3/1 and SPT24, respectively, with no significant difference being seen between the two clones (P = 0.839), and there was good consistency between these two antibodies in differentiating breast and pulmonary carcinomas (kappa value 0.905; P < 0.001). Both clones showed high specificity but relatively low sensitivity. Cytoplasmic TTF-1 expression was detected in 44 IBCs by 8G7G3/1, and this particular expression pattern was an independent adverse prognostic factor.
CONCLUSIONS: Both TTF-1 antibodies (clones 8G7G3/1 and SPT24) were useful in differentiating breast from pulmonary carcinomas. Nuclear expression of TTF-1 was detected in IBCs by 8G7G3/1, but not by SPT24. Cytoplasmic expression of 8G7G3/1 was seen in IBC for the first time, and was an independent unfavourable prognostic factor.

Zhou DM, Sun Y, Li XH
[Diagnostic value of microtubule-associated protein-2 in small cell lung carcinoma: an analysis of 240 biopsy cases].
Zhonghua Bing Li Xue Za Zhi. 2013; 42(5):321-4 [PubMed] Related Publications
OBJECTIVE: To investigate the diagnostic value of microtubule-associated protein-2 (MAP-2) in biopsy of small cell lung carcinoma (SCLC).
METHODS: Immunohistochemical technique was applied to detect the expression of synaptophysin (Syn), chromogranin A (CgA), CD56, MAP-2 and TTF-1 in 240 cases of SCLC from 2008 to 2011 in this hospital.
RESULTS: The positive rate of MAP-2 expression in SCLC was 95.8% (230/240), which was much higher than that of Syn (57.1%, 137/240), CgA (38.8%, 93/240) and CD56 (89.2%, 214/240). The sensitivity and accuracy of MAP-2 (99.1%, 95.4%) expression were also higher than those of Syn (58.3%, 42.5%), CgA (39.9%, 42.5%) and CD56 (91.5%, 87.9%).
CONCLUSIONS: MAP-2 is a new neuroendocrine marker with higher sensitivity and accuracy, and thus recommended to be added to the immunohistochemical panel for the diagnosis of SCLC.

Gahr S, Stoehr R, Geissinger E, et al.
EGFR mutational status in a large series of Caucasian European NSCLC patients: data from daily practice.
Br J Cancer. 2013; 109(7):1821-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The prognosis of metastatic non-small cell lung cancer (NSCLC) is still poor. Activating epithelial growth factor receptor (EGFR) mutations are important genetic alterations with dramatic therapeutical implications. Up to now, in contrast to Asian populations only limited data on the prevalence of those mutations are available from patients with Caucasian and especially European ethnicity.
METHODS: In this multicentre study, 1201 unselected NSCLC patients from Southern Germany were tested in the daily clinical routine for EGFR mutation status.
RESULTS: Activating EGFR mutations were found in 9.8% of all tumours. Mutations in exons 18, 19 and 21 accounted for 4.2%, 61.9% and 33.1% of all mutations, respectively. Non-smokers had a significantly higher rate of EGFR mutations than smokers or ex-smokers (24.4% vs 4.2%; P<0.001). Non-lepidic-non-mucinous adenocarcinomas (G2) accounted for 45.5% of all activating EGFR mutations and 3.5% of all squamous cell carcinomas were tested positive. Thyroid transcription factor 1 protein expression was significantly associated with EGFR mutational status.
CONCLUSION: These comprehensive data from clinical routine in Germany add to the knowledge of clinical and histopathological factors associated with EGFR mutational status in NSCLC.

Tsai LH, Chen PM, Cheng YW, et al.
LKB1 loss by alteration of the NKX2-1/p53 pathway promotes tumor malignancy and predicts poor survival and relapse in lung adenocarcinomas.
Oncogene. 2014; 33(29):3851-60 [PubMed] Related Publications
LKB1 loss is a frequent homozygous deletion and/or gene mutation found in lung adenocarcinomas. However, few cases of LKB1 loss by either deletion or mutation are seen in Asian patients. Our preliminary data showed that LKB1 loss was associated with p53 mutation in lung tumors from Taiwanese adenocarcinoma patients and p53 transcription is directly regulated by NKX2-1. Therefore, we hypothesized that LKB1 loss could occur due to aberration of p53 regulation mediated by NKX2-1. In the present study, 16 lung adenocarcinoma cell lines were investigated to determine if LKB1 transcription could be deregulated by NKX2-1-mediated p53 aberration. Mechanistic studies indicated that LKB1 was directly upregulated by p53 and that NKX2-1-mediated p53 expression may positively regulate LKB1 expression in p53 wild-type cells. However, in p53-mutated cells, LKB1 transcription was deregulated by NKX2-1 via suppression of SP1 binding onto the LKB1 promoter. Therefore, the action of the NKX2-1/p53 pathway on LKB1 loss differed in p53 wild-type versus p53-mutated cells. As expected, soft-agar growth and invasion capability was significantly reduced by ectopic expression of NKX2-1 in p53 wild-type cells, but it was markedly elevated by silencing NKX2-1 in p53-mutated cells. Similar reciprocal observations were also seen in lung tumors from lung adenocarcinoma patients with either wild-type or mutated p53 tumors. Cox regression analysis showed that patients with low-LKB1 tumors had poorer overall survival (OS) and relapse-free survival (RFS) when compared with patients with high-LKB1 tumors. In p53 wild-type patients, shorter OS and RFS periods were predicted for low-NKX2-1/low-LKB1 tumors than for high-NKX2-1/high-LKB1 tumors. In patients with p53-mutated tumors, poorer OS and RFS were predicted for high-NKX2-1/low-LKB1 tumors than for low-NKX2-1/high-LKB1 tumors. In summary, losses of LKB1 at the transcriptional level by altered activity of the NKX2-1/p53 pathway may promote tumor malignancy and poor patient outcome.

Aulakh KS, Chisholm CD, Smith DA, Speights VO
TTF-1 and napsin A do not differentiate metastatic lung adenocarcinomas from primary esophageal adenocarcinomas: proposal of a novel staining panel.
Arch Pathol Lab Med. 2013; 137(8):1094-8 [PubMed] Related Publications
CONTEXT: When adenocarcinomas arise within the esophagus, particularly when located away from the gastroesophageal junction, it may be important in some patients to differentiate between a primary esophageal adenocarcinoma and metastasis from another site. Lung adenocarcinoma is one tumor that has been reported to frequently metastasize to the esophagus.
OBJECTIVES: To create a panel of immunohistochemical markers that can reliably distinguish between an esophageal and pulmonary primary; within the gastrointestinal pathology literature, including published articles and textbooks, common lung immunohistochemical markers, such as TTF-1, are assumed to be negative in esophageal adenocarcinoma, yet, to our knowledge, no study has yet investigated the veracity of that presumption.
DESIGN: In this study, 24 cases each of pulmonary and esophageal adenocarcinomas were stained with TTF-1, napsin A, CDX2, 34βE12, N-cadherin, and IMP3 in an attempt to define an optimal panel for differentiation. Esophageal adenocarcinomas occurring at the gastroesophageal junction were excluded in this study because a gastric primary tumor cannot be excluded in those cases.
RESULTS: Surprisingly, TTF-1 and napsin A were positive in similar proportions of tumors from both sites. Those markers that differentiated statistically between esophageal and pulmonary adenocarcinoma were IMP3, CDX2, and N-cadherin.
CONCLUSIONS: When differentiating the origin of a tumor as either esophageal or pulmonary, an immunohistochemical panel consisting of IMP3, CDX2, and N-cadherin is superior to either TTF-1 or napsin A.

Jinkala SR, Ganesh RN, Badhe BA, et al.
Primary Merkel cell neuroendocrine carcinoma of head and neck: uncommon manifestations.
Pathology. 2013; 45(5):510-3 [PubMed] Related Publications

Mu D
The complexity of thyroid transcription factor 1 with both pro- and anti-oncogenic activities.
J Biol Chem. 2013; 288(35):24992-5000 [PubMed] Free Access to Full Article Related Publications
After the original identification of thyroid transcription factor 1 (TTF-1 or NKX2-1) biochemical activity as a transcriptional regulator of thyroglobulin in 1989, the bulk of the ensuing research has concentrated on elucidating the roles of NKX2-1 in the development of lung and thyroid tissues. Motivated by its specific expression pattern, pathologists adopted the NKX2-1 immunoreactivity to distinguish pulmonary from nonpulmonary nonthyroid adenocarcinomas. Interestingly, the concept of NKX2-1 as an active participant in lung tumorigenesis did not take hold until 2007. This minireview contrasts the recent advancements of NKX2-1-related observations primarily in the realm of pulmonary malignancies.

Chen PM, Wu TC, Wang YC, et al.
Activation of NF-κB by SOD2 promotes the aggressiveness of lung adenocarcinoma by modulating NKX2-1-mediated IKKβ expression.
Carcinogenesis. 2013; 34(11):2655-63 [PubMed] Related Publications
Magnesium superoxide dismutase (SOD2) has been shown to cause dysfunction of p53 transcriptional activity, whereas, in turn, SOD2 expression is regulated by p53 to modulate lung tumorigenesis. In this study, we found that the level of SOD2 expression in a panel of lung cancer cells was negatively correlated with that of NK2 homeobox 1 (NKX2-1) but was not associated with p53 status. Mechanistic studies indicated that a decrease in NKX2-1 caused by SOD2-activated IKKβ transcription was achieved by derepression of binding of Sp1 to the IKKβ promoter. Immunoprecipitation, glutathione S-transferase pull-down experiments and electrophoretic mobility shift assays demonstrated a direct interaction between NKX2-1 and Sp1, blocking Sp1-mediated IKKβ transcription. SOD2-mediated nuclear factor-kappaB activation, via elevation of IKKβ transcription, promoted anchorage-independent soft-agar growth, invasion and xenograft tumor formation, because of development of the epithelial-to-mesenchymal transition. The expression level of NKX2-1 messenger RNA was negatively associated with the extent of SOD immunostaining and the IKKβ messenger RNA expression level in lung tumors. The extent of SOD2 immunostaining and IKKβ messenger RNA levels may independently predict overall survival and relapse-free survival in lung adenocarcinoma patients. In summary, we found that SOD2 activates nuclear factor-kappaB signaling by increasing IKKβ transcription, which results in progression of lung adenocarcinoma and poorer patient outcomes. We suggest that IKKβ may potentially be targeted to improve outcomes in patients with SOD2-positive tumors.

Brunnström H, Johansson L, Jirström K, et al.
Immunohistochemistry in the differential diagnostics of primary lung cancer: an investigation within the Southern Swedish Lung Cancer Study.
Am J Clin Pathol. 2013; 140(1):37-46 [PubMed] Related Publications
OBJECTIVES: To assess immunohistochemical (IHC) stains differentially expressed between different types of lung cancer.
METHODS: We evaluated 16 different IHC stains in 209 prospectively included, surgically treated primary lung cancers, including 121 adenocarcinomas, 65 squamous cell carcinomas, 15 large-cell carcinomas, 5 adenosquamous carcinomas, 2 sarcomatoid carcinomas, and 1 small-cell carcinoma, using the tissue microarray technique.
RESULTS: Cytokeratin 5 (CK5) and P63 were both positive in 10% or more of the cells in 97% of the squamous cell carcinomas, with the former being positive (<10% of the cells) in only 2 non-squamous cell carcinomas. Thyroid transcription factor 1 (TTF1) and napsin A were positive in 10% or more of the cells in 88% and 87% of the adenocarcinomas, respectively, with 94% of the adenocarcinomas being positive in at least 1 marker. Fifteen percent of the adenocarcinomas were positive for estrogen receptor.
CONCLUSIONS: CK5, TTF1, and napsin A are sensitive markers for squamous cell carcinoma and adenocarcinoma of the lung.

Yamaguchi T, Hosono Y, Yanagisawa K, Takahashi T
NKX2-1/TTF-1: an enigmatic oncogene that functions as a double-edged sword for cancer cell survival and progression.
Cancer Cell. 2013; 23(6):718-23 [PubMed] Related Publications
Emerging evidence indicates that NKX2-1, a homeobox-containing transcription factor also known as TTF-1, plays a role as a "lineage-survival" oncogene in lung adenocarcinomas. In T cell acute lymphoblastic leukemia, gene rearrangements lead to aberrant expression of NKX2-1/TTF-1. Despite accumulating evidence supporting its oncogenic role, it has become apparent that NKX2-1/TTF-1 expression also has biological and clinical functions in the opposite direction that act against tumor progression. Herein, we review recent findings showing these enigmatic double-edged characteristics, with special attention given to the roles of NKX2-1/TTF-1 in lung development and carcinogenesis.

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