RHOH

Gene Summary

Gene:RHOH; ras homolog family member H
Aliases: TTF, ARHH
Location:4p14
Summary:The protein encoded by this gene is a member of the Ras superfamily of guanosine triphosphate (GTP)-metabolizing enzymes. The encoded protein is expressed in hematopoietic cells, where it functions as a negative regulator of cell growth and survival. This gene may be hypermutated or misexpressed in leukemias and lymphomas. Chromosomal translocations in non-Hodgkin's lymphoma occur between this locus and B-cell CLL/lymphoma 6 (BCL6) on chromosome 3, leading to the production of fusion transcripts. Alternative splicing in the 5' untranslated region results in multiple transcript variants that encode the same protein. [provided by RefSeq, May 2013]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:rho-related GTP-binding protein RhoH
Source:NCBIAccessed: 16 March, 2017

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 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.

  • Lymphocytes
  • Diffuse Large B-Cell Lymphoma
  • Follicular Lymphoma
  • Gene Rearrangement
  • Proto-Oncogene Proteins c-pim-1
  • Proto-Oncogene Proteins
  • Cytidine Deaminase
  • Base Sequence
  • B-Lymphocytes
  • Polymerase Chain Reaction
  • Cancer Gene Expression Regulation
  • Molecular Sequence Data
  • myc Genes
  • DNA Mutational Analysis
  • Nucleic Acid Regulatory Sequences
  • Somatic Hypermutation, Immunoglobulin
  • Immunoglobulin Heavy Chains
  • Neoplastic Cell Transformation
  • Genomic Instability
  • Mutation
  • DNA-Binding Proteins
  • RTPCR
  • ARHH
  • Chronic Lymphocytic Leukemia
  • Chromosome 4
  • rac1 GTP-Binding Protein
  • B-Cell Lymphoma
  • Transcription Factors
  • Non-Hodgkin Lymphoma
  • Immunoglobulin Variable Region
  • rho GTP-Binding Proteins
  • Chromosome 3
  • ras Proteins
  • Proto-Oncogene Proteins c-bcl-6
  • Skin Cancer
  • Translocation
  • Splenic Neoplasms
  • FISH
  • Neoplasm Proteins
  • Cultured Cells
  • PAX5 Transcription Factor
Tag cloud generated 16 March, 2017 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: RHOH (cancer-related)

Bi Y, Deng Y, Li S, et al.
Immunophenotypic and prognostic analysis of PAX8 and TTF-1 expressions in neuroendocrine carcinomas of thymic origin: A comparative study with their pulmonary counterparts.
J Surg Oncol. 2016; 114(6):697-702 [PubMed] Related Publications
OBJECTIVES: To investigate the immunoreactivity of TTF-1 and PAX8 in neuroendocrine carcinoma of thymic (TNEC) and pulmonary origins (PNEC), and whether their immunophenotyping could be used to distinguish between NEC of the two sites, as well as prognosis of patients with TNEC.
METHODS: Twenty-two cases of TNEC and 20 cases of PNEC were selected for immunohistochemical analysis using PAX8 and TTF-1. Clinical data and follow-up information were obtained for survival analyses.
RESULTS: TTF-1 immunoreactivity was seen in 19 PNEC cases (95%) and 13 TNEC cases (59.1%). PAX8 was negative in all pulmonary tumors while positive in 19 thymic cases (86.4%). TTF-1 positivity was associated with high sensitivity but low specificity for PNEC, and adding PAX8 negativity significantly increased the specificity. PAX8 positivity alone showed essentially 100% specificity and 86.4% sensitivity for TNEC. Survival analysis showed lung metastasis as a significant prognostic factor in TNEC.
CONCLUSION: Our study demonstrated that TTF-1/PAX8 immunophenotyping may be helpful for differential diagnosis of NECs of pulmonary and thymic origins. TTF-1+/PAX8- immunophenotyping showed high specificity for PNECs, while PAX8+ alone showed a good diagnostic accuracy for TNEC. Lung metastasis was a predictive factor that associated with survival of TNEC patients. J. Surg. Oncol. 2016;114:697-702. © 2016 Wiley Periodicals, Inc.

Czapiewski P, Gorczyński A, Haybaeck J, et al.
Expression pattern of ISL-1, TTF-1 and PAX5 in olfactory neuroblastoma.
Pol J Pathol. 2016; 67(2):130-5 [PubMed] Related Publications
Olfactory neuroblastoma (ONB) is a rare neoplasm of the sinonasal area with neuroendocrine differentiation. ISL-1, TTF-1 and PAX5 are transcription factors that are frequently upregulated in tumors showing neuroendocrine differentiation. The aim of our study was to evaluate these markers in a group of ONBs. We included 11 ONBs from 4 large university hospitals. Immunohistochemical expression of TTF-1, PAX5 and ISL-1 was evaluated. TTF-1, ISL-1 and PAX5 were expressed in 3/11 cases (27.27%, h-score: 3-45), 7/11 cases (63.64%, h-score: 23-200), and in 3/11 cases (27.77%, h-score 3-85), respectively. The patient with the strongest PAX5 reactivity exhibited an aggressive clinical course with rapid dissemination to the spine and death shortly after the diagnosis. No significant correlation in the expression of PAX5 and TTF-1 ( = 0.43; p = 0.18) was observed. ISL-1 is widely expressed in tumors with neuroendocrine differentiation and therefore of limited value in their differential diagnosis. TTF-1 positivity does not exclude the diagnosis of primary ONB, although usually only a small percentage of cells are positive. PAX5 expression is infrequent (27.27%) in ONB; however, if present it can be associated with a very aggressive clinical course.

Ozluk Y, Firat P, Yegen G, et al.
EGFR mutation testing using archival-stained smears in non-small cell lung carcinoma.
Cytopathology. 2017; 28(1):35-45 [PubMed] Related Publications
OBJECTIVE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown benefits regarding progression-free and overall survival in patients whose tumours show EGFR mutations. Most patients' lung cancer is metastatic when detected. Small tissue samples and cytological materials are widely used in diagnosis. The aim of the present study was to compare the EGFR mutation analysis results between cytology, small biopsies and resections.
METHODS: Archival material for EGFR testing was reviewed. Cell blocks and/or stained smears and tissue blocks were used where appropriate. The tumour cell count and percentage were recorded as well as the DNA content. The influence of TTF-1 immunoreactivity on EGFR testing was also investigated.
RESULTS: The study cohort included 300 unpaired specimens of 84 resections, 83 small biopsies and 133 cytological materials. EGFR mutation rates did not differ significantly for cytology, small biopsy and resections (P > 0.05). The higher tumour cell percentage in FNAs than in exfoliative cytology did not affect the EGFR mutation status. EGFR mutation rates were similar when either slides or cell blocks were used. Cytology slides revealed a higher tumour cell content and DNA concentration than the cell blocks. May-Grünwald-Giemsa (MGG)-stained smears had higher rates of the EGFR mutation than the Papanicolaou (Pap)-stained slides (P < 0.05). Tumours with negative immunoreactivity for TTF-1 are less likely to have an EGFR mutation (P < 0.05).
CONCLUSIONS: Cytological materials can be used successfully for mutation analysis in lung cancer.

Vallonthaiel AG, Jain D, Madan K, Arava S
Pulmonary adenocarcinoma with signet ring features: Detailed cytomorphologic analysis.
Diagn Cytopathol. 2016; 44(7):607-11 [PubMed] Related Publications
BACKGROUND: Signet ring cell feature in lung adenocarcinoma is no longer considered a distinct subtype, but as a cytologic change that may occur in association with multiple histological patterns. Cases with signet ring cells show a strong association with Anaplastic Lymphoma Kinase (ALK) gene fusions and solid pattern.
METHODS: The cytomorphological findings of pulmonary adenocarcinoma with signet ring features (PASRF) was studied. Cases of pulmonary adenocarcinoma which showed presence of signet ring cells either on cytology or histology were included in the study.
RESULTS: Out of 218 pulmonary adenocarcinomas diagnosed during the study period, 11 cases showed presence of signet ring cells (11/218). Out of the 11 cases, 7 had paired histology and cytology available, while the remaining 4 did not have a corresponding cytology sample. Majority of the cases (6/11) showed signet ring cells in more than 90% of the tumor area. All cases showed solid growth pattern. TTF-1 was positive in all the cases. Immunopositivity for ALK was seen in seven cases. The cytology smears showed single cells and clusters of signet ring cells, with either intracytoplasmic mucin vacuole and eccentric nucleus or histiocyte-like finely vacuolated cytoplasm with round nucleus and prominent nucleoli, the latter resembling alveolar macrophages.
CONCLUSION: PASRF is commonly associated with a solid histologic pattern. Cases with predominant histiocyte-like pattern may be misdiagnosed on cytology; hence a high index of suspicion is required for an accurate diagnosis. Diagn. Cytopathol. 2016;44:607-611. © 2016 Wiley Periodicals, Inc.

Zhao W, Choi YL, Song JY, et al.
ALK, ROS1 and RET rearrangements in lung squamous cell carcinoma are very rare.
Lung Cancer. 2016; 94:22-7 [PubMed] Related Publications
OBJECTIVES: Chromosomal rearrangements of ALK and ROS1 genes in non-small cell lung carcinoma (NSCLC) define a molecular subgroup of lung adenocarcinoma (ADC) that is amenable to targeted therapy with tyrosine kinase inhibitors (TKIs) crizotinib. Emerging clinical studies have demonstrated that patients with RET-rearranged NSCLC may also benefit from existing RET TKIs, including cabozantinib and vandetanib. However, the reported cases of lung squamous cell carcinomas (SCC) harboring gene rearrangements have been detected via fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) from materials such as biopsy or resection. Fusion events identified in lung SCC raise the question of whether this histologic subtype should also be evaluated for merit molecular testing. This work was undertaken to study the prevalence of lung SCC harboring ALK, ROS1, and RET translocations.
MATERIALS AND METHODS: Squamous cell carcinomas were confirmed using both histological examination by pathologists and immunohistochemistry analysis with positive staining of P63 and CK5/6 combined with negative CK7 and TTF-1 staining. 214 samples from surgically resected patient tissues were used to search for ALK, ROS1, and RET rearrangements by a NanoString analysis method. Fusion events were detected in a single-tube, multiplex assay system that relied on a complementary strategy of interrogation of 3' gene overexpression and detection of specific fusion transcript variants.
RESULTS AND CONCLUSION: ALK, ROS1 or RET gene rearrangements appeared 0 times out of 214 cases of lung SCC. Our data revealed that these fusions may be very rare in lung squamous cancer. The molecular screening strategy should therefore be focused on lung adenocarcinoma as the current National Comprehensive Cancer Network (NCCN) guideline recommends.

Wood LW, Cox NI, Phelps CA, et al.
Thyroid Transcription Factor 1 Reprograms Angiogenic Activities of Secretome.
Sci Rep. 2016; 6:19857 [PubMed] Free Access to Full Article Related Publications
Through both gain- and loss-of-TTF-1 expression strategies, we show that TTF-1 positively regulates vascular endothelial growth factor (VEGF) and that the VEGF promoter element contains multiple TTF-1-responsive sequences. The major signaling receptor for VEGF, i.e VEGFR2, also appears to be under a direct and positive regulation of TTF-1. The TTF-1-dependent upregulation of VEGF was moderately sensitive to rapamycin, implicating a partial involvement of mammalian target of rapamycin (mTOR). However, hypoxia did not further increase the secreted VEGF level of the TTF-1(+) lung cancer cells. The TTF-1-induced VEGF upregulation occurs in both compartments (exosomes and exosome-depleted media (EDM)) of the conditioned media. Surprisingly, the EDM of TTF-1(+) lung cancer cells (designated EDM-TTF-1(+)) displayed an anti-angiogenic activity in the endothelial cell tube formation assay. Mechanistic studies suggest that the increased granulocyte-macrophage colony-stimulating factor (GM-CSF) level in the EDM-TTF-1(+) conferred the antiangiogenic activities. In human lung cancer, the expression of TTF-1 and GM-CSF exhibits a statistically significant and positive correlation. In summary, this study provides evidence that TTF-1 may reprogram lung cancer secreted proteome into an antiangiogenic state, offering a novel basis to account for the long-standing observation of favorable prognosis associated with TTF-1(+) lung adenocarcinomas.

El Hag M, Schmidt L, Roh M, Michael CW
Utility of TTF-1 and Napsin-A in the work-up of malignant effusions.
Diagn Cytopathol. 2016; 44(4):299-304 [PubMed] Related Publications
BACKGROUND: Similar to TTF-1, Napsin-A is recently used increasingly to differentiate between pulmonary adenocarcinoma (P-ADC) and extra-pulmonary adenocarcinoma (EP-ADC). The aim of this study was to compare the performance of TTF-1 and Napsin-A in determining the primary origin of adenocarcinoma in malignant serous effusion.
METHODS: Following IRB approval, cellblocks from 139 cases of malignant serous effusions of histologically or clinically determined origin including: 26 P-ADC, 108 EP-ADC, 2 pulmonary squamous cell carcinoma (P-SQC), and 3 pulmonary small cell carcinoma (P-SCC) were retrieved. Each case was stained with Napsin-A and TTF-1 and evaluated for positivity and intensity of staining.
RESULTS: Napsin-A and TTF-1 stained positive in 17/26 (65%) and 14/26 (54%) of P-ADC and in 2/108 (1.8%) and 0/108 (0%) of EP-ADC with a PPV of 89 and 100%, respectively. In combination, they positively stained 18/26 (70%) of P-ADC with a PPV of 90%. Out of 9 poorly differentiated P-ADC, 7 (78%) stained positive for Napsin-A, while 4 (45%) were reactive for TTF-1. Both Napsin-A and TTF-1 were negative in P-SQC, while P-SCC reacted positively for TTF-1 in 2/3 (66%) of cases and none for Napsin-A.
CONCLUSION: Napsin-A and TTF-1 are both useful markers in distinguishing P-ADC from EP-ADC. However, Napsin-A performed better in poorly differentiated P-ADC and its mimickers. The nuclear staining of TTF-1 is crispier and much easier to interpret than Napsin-A cytoplasmic stain. An antibody panel including TTF-1 and Napsin-A or a dual stain will be very helpful in determining the origin of metastatic adenocarcinoma in serous effusion.

Suda K, Murakami I, Sakai K, et al.
Heterogeneity in resistance mechanisms causes shorter duration of epidermal growth factor receptor kinase inhibitor treatment in lung cancer.
Lung Cancer. 2016; 91:36-40 [PubMed] Related Publications
OBJECTIVES: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are used as a first line therapy for metastatic lung cancer harboring somatic EGFR mutation. However, acquisition of resistance to these drugs is almost inevitable. T790M (threonine to methionine substitution at codon 790 of the EGFR gene) and MET amplification are well-known resistance mechanisms, and we previously demonstrated that three of six autopsied patients showed inter-tumor heterogeneity in resistance mechanisms by analyzing T790M and MET gene copy number (Suda et al., 2010). To further elucidate the role of heterogeneity in acquired resistance, here we performed further analyses including additional five patients.
MATERIALS AND METHODS: We analyzed somatic mutations in 50 cancer-related genes for 26 EGFR-TKI refractory lesions from four autopsied patients using target sequencing. MET and ERBB2 copy numbers were analyzed by real-time PCR. Data for additional one patient was obtained from our recent study (Suda et al., 2015). Relationship between heterogeneity in resistance mechanism(s) and time to treatment failure (TTF) of EGFR-TKI and post-progression survival (PPS) were analyzed.
RESULTS AND CONCLUSION: We observed heterogeneity of resistance mechanisms in two of four patients analyzed (T790M+MET gene copy number gain, and mutant EGFR loss+unknown). We also identified quantitative heterogeneity in EGFR T790M mutation ratio among EGFR-TKI refractory lesions. In analyzing patient outcomes, we found that patients who developed multiple resistance mechanisms had shorter TTF compared with those who developed single resistance mechanism (p=0.022). PPS after EGFR-TKI treatment failure was compatible between these two groups (p=0.42). These findings further our understanding of acquired resistance mechanisms to EGFR-TKIs, and may lead to better treatment strategies after acquisition of resistance to first generation EGFR-TKIs in lung cancer patients with EGFR mutations.

Ida L, Yamaguchi T, Yanagisawa K, et al.
Receptor tyrosine kinase-like orphan receptor 1, a target of NKX2-1/TTF-1 lineage-survival oncogene, inhibits apoptosis signal-regulating kinase 1-mediated pro-apoptotic signaling in lung adenocarcinoma.
Cancer Sci. 2016; 107(2):155-61 [PubMed] Free Access to Full Article Related Publications
We previously identified receptor tyrosine kinase-like orphan receptor 1 (ROR1) as a transcriptional target of the NKX2-1/TTF-1 lineage-survival oncogene in lung adenocarcinoma. ROR1 consequently sustains a favorable balance between pro-survival phosphatidylinositol 3-kinase-protein kinase B and pro-apoptotic apoptosis signal-regulating kinase 1 (ASK1)-p38MAPK signaling. In contrast to recent advances in understanding how ROR1 sustains pro-survival signaling, the mechanism of ROR1 repression of pro-apoptotic signaling remains rather elusive. In the present study, we investigated the underlying mechanism of ROR1-mediated inhibition of the ASK1-p38MAPK signaling pathway. Growth inhibition mediated by siROR1 was partially but significantly alleviated by ASK1 co-knockdown in lung adenocarcinoma cell lines. Also, ASK1 phosphorylation at Thr845, which reflects its activated state, was clearly inhibited by ROR1 overexpression in both steady state and oxidative stress-elicited conditions in MSTO-211H cells. In addition, we found that ROR1 was physically associated with ASK1 at the C-terminal serine threonine-rich domain of ROR1. Furthermore, ROR1 kinase activity was shown to be required to repress the ASK1-p38 axis and oxidative stress-induced cell death. The present findings thus support our notion that ROR1 sustains lung adenocarcinoma survival, at least in part, through direct physical interaction with ASK1 and consequential repression of the pro-apoptotic ASK1-p38 axis in a ROR1 kinase activity-dependent manner.

Squillaci S, Pitino A, Spairani C, et al.
Mucinous Variant of Follicular Carcinoma of the Thyroid Gland: Case Report and Review of the Literature.
Int J Surg Pathol. 2016; 24(2):170-6 [PubMed] Related Publications
The rare reports of mucinous variant of follicular carcinoma of the thyroid gland have not provided enough evidence to support the recognition of these tumors as a distinct clinicopathologic entity or to understand their etiopathogenesis. We report the fourth case of mucinous variant of follicular carcinoma displaying a minimally invasive tumor with diffuse expression of thyroglobulin, TTF-1, CD56, PAX-8, cytokeratins 7 and 19, in the absence of monoclonal carcinoembryonic antigen (CEA), cytokeratin 20, chromogranin, HBME-1, P63 expression, and BRAF gene mutation, in a 51-year-old woman who is alive without signs of disease 13 months after total thyroidectomy, bilateral neck dissection, and radioactive iodine. Herein, fine-needle aspiration cytology disclosed "worrisome" cytologic features consisting of large epithelial cells arranged in clusters or singularly, with high nucleocytoplasmic ratio, nuclear grooves and evident nucleoli which were shared by those of mucin-producing papillary thyroid carcinoma. Therefore, knowledge of the cytological and histopathological spectrum of this lesion is important to avoid misdiagnosis. The morphologic clues leading to the correct diagnosis of mucinous variant of follicular neoplasm have been correlated with the data of the literature, and the differential diagnosis is briefly discussed.

Huo Z, Wu H, Li J, et al.
Primary Pulmonary Mucoepidermoid Carcinoma: Histopathological and Moleculargenetic Studies of 26 Cases.
PLoS One. 2015; 10(11):e0143169 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Pulmonary mucoepidermoid carcinoma (PMEC) is an uncommon neoplasm of the lung and the main salivary gland-type lung carcinoma. The aims of this study were to review the clinicopathological and immunohistochemical features of PMEC and characterize the genetic events in PMEC.
METHODS: We reviewed the pathology cases in our hospital and found 34 initially diagnosed PMEC cases, 26 of which were confirmed as PMEC after excluding 8 cases of MEC-like pulmonary carcinoma. The clinicopathological characteristics of the 26 PMEC cases and the 8 cases of MEC-like pulmonary carcinoma were retrospectively reviewed. MAML2 rearrangement was detected by fluorescence In Situ Hybridization (FISH). Immunostains of ALK, calponin, collagen IV, CK7, EGFR, HER2, Ki-67, Muc5Ac, p63, p40, and TTF-1 were performed. DNA was extracted from 23 cases of PMEC. Mutation profiling of the EGFR, KRAS, BRAF, ALK, PIK3CA, PDGFRA, and DDR2 genes were carried out using next-generation sequencing (NGS), Sanger sequencing, and quantitative polymerase chain reaction (QPCR) in 9 successfully amplified cases.
RESULTS: Twenty-six cases of PMEC (18 low-grade, 8 high-grade) included 13 men and 13 women aged 12-79 years. Twenty-two cases had a central/endobronchial growth pattern, and 4 cases had a peribronchial growth pattern. Immunohistochemically, CK7, Muc5Ac, p40, and p63 were positive in all cases (26/26);EGFR was positive in 11 cases (11/26); TTF-1, Calponin, HER2 and ALK were negative in all cases (0/26). MAML2 rearrangement was identified in 12 of 18 PMEC cases. No mutations were detected in any of the 7 genes in the 9 cases that qualified for mutation analysis. Twenty-three PMEC patients had follow-up information with a median interval of 32.6 months. Both the 5- and 10-year overall survival rates (OS) were 72.1%, and a high-grade tumor was an adverse prognostic factor in PMEC. There were 8 cases of MEC-like pulmonary carcinoma aged 36-78 years: 2 cases were located in the bronchus, and 6 cases were located in the lung. p63 and TTF-1 were positive in all cases (8/8), p40 was positive in 5 cases (5/8), and ALK was positive in 5 cases (5/8). No cases of MAML2 rearrangement were detected, but there were 5 cases of ALK rearrangement.
CONCLUSIONS: PMEC is a primary malignant pulmonary tumor with a relatively good prognosis that is historically characterized by the presence of mucous cells and a lack of keratinization. There are distinct differences between PMEC and MEC-like pulmonary carcinoma in tumor location preference, immunophenotype, and molecular genetics, and the differential diagnosis is critical due to the therapeutic and prognostic considerations.

Inoue Y, Matsuura S, Kurabe N, et al.
Clinicopathological and Survival Analysis of Japanese Patients with Resected Non-Small-Cell Lung Cancer Harboring NKX2-1, SETDB1, MET, HER2, SOX2, FGFR1, or PIK3CA Gene Amplification.
J Thorac Oncol. 2015; 10(11):1590-600 [PubMed] Related Publications
INTRODUCTION: Gene amplification is an important genetic change in cancer cells. We investigated the prevalence, clinicopathological characteristics, and prognostic value of NKX2-1 (also known as TTF-1), SETDB1, MET, HER2, SOX2, FGFR1, and PIK3CA amplification in Japanese patients with non-small-cell lung cancer (NSCLC).
METHODS: The copy numbers of the seven above-mentioned genes were assessed using fluorescence in situ hybridization in a tissue microarray containing 282 surgically resected NSCLC specimens (164 adenocarcinoma [AC], 99 squamous cell carcinoma [SCC], and 19 others). Clinicopathological information were obtained from the medical records.
RESULTS: NKX2-1, SETDB1, MET, HER2, SOX2, FGFR1, and PIK3CA gene amplification were observed in 30 of 277 (10.8%), 16 of 280 (5.7%), 38 of 278 (13.7%), 8 of 270 (3.0%), 34 of 278 (12.2%), 18 of 282 (6.4%), and 53 of 278 (19.1%) cases, respectively. Coamplification was detected in 16 of 156 (10.3%) AC patients and 35 of 93 (37.6%) SCC patients (p < 0.0001). NKX2-1 amplification was significantly related to an AC histology (p = 0.004), whereas SOX2, FGFR1, and PIK3CA amplifications were related to a SCC histology (p < 0.0001). Within the ACs, NKX2-1 and SETDB1 amplifications were markers of a shorter survival period. A multivariate Cox proportional hazards model revealed that NKX2-1 amplification was an independent predictor of poor survival (hazard ratio, 2.938; 95% confidence interval, 1.434-6.022; p = 0.003). Coamplification had impact on patient outcome in AC but not in entire NSCLC and SCC.
CONCLUSIONS: The amplification status differed among the histological types of NSCLC. NKX2-1 amplification was an independent and the most practically important predictor of a poor prognosis among Japanese patients with AC.

Ding M, Li X, Qiu T
Combination of multiple gene markers to detect circulating tumor cells in the peripheral blood of patients with non-small cell lung cancer using real-time PCR.
Genet Mol Res. 2015; 14(4):13033-40 [PubMed] Related Publications
Our study aims to determine the clinical significance of human telomerase reverse transcriptase (hTERT), S-phase kinase-associated protein 2 (Skp2) and thyroid transcription factor-1 (TTF-1) mRNA expressions in peripheral blood (PB) of patients with non-small cell lung cancer (NSCLC). Real-time polymerase chain reaction was used to investigate the gene expressions of hTERT, Skp2, TTF-1 as in the PB of 60 patients with NSCLC and 20 benign lung diseases. Statistical analyses were performed to examine the correlation between the expression of these mRNA markers and the clinical pathological features of NSCLC. We found that hTERT, Skp2, and TTF-1 were overexpressed in the PB of NSCLC patients, and demonstrated high specificity as well as sensitivity when used for NSCLC diagnosis. Significant correlation was observed between disease stage and the three markers (P < 0.05). This study suggests that the genes hTERT, Skp2, and TTF-1 play important roles in tumor genesis and development, and can be used as diagnosis markers in NSCLC patients. The expression of three markers in combination can significantly improve the sensitivity and accuracy of diagnosis relative to single marker diagnosis, and provides a reliable method to detect CTCs in the PB. Additionally, these markers can also be used as diagnostic markers for clinical stages of NSCLC.

Cowan ML, Li QK, Illei PB
CDX-2 Expression in Primary Lung Adenocarcinoma.
Appl Immunohistochem Mol Morphol. 2016; 24(1):16-9 [PubMed] Related Publications
Adenocarcinoma with enteric differentiation is a rare subtype of lung adenocarcinoma that is recognized as a variant type of primary adenocarcinoma in the 2015 World Health Organization classification of lung tumors. Published immunohistochemistry studies show variable staining pattern for CDX-2 ranging from positivity in 71% of the cases to no staining. As little is known about CDX-2 expression in lung adenocarcinomas lacking histologic features of enteric differentiation, our aim was to determine the rate of CDX-2 positivity in non-enteric-type lung adenocarcinomas. We performed immunohistochemistry for CDX-2, CK7, CK20, TTF-1, napsin A, and p40 using 4-μm sections of a previously constructed tissue microarray containing 93 primary lung adenocarcinomas that lack morphologic evidence of enteric differentiation. The cohort included 22 well, 54 moderately, and 17 poorly differentiated tumors (55 female, 38 male; age range: 42 to 86, median: 64.5). All 93 tumors were strongly CK7 positive, whereas variable CK20 staining was seen in 4 tumors (1 strong, 1 moderate, and 2 focal). Both TTF-1 and napsin A were positive in 81 of 93 (87%) tumors with only 6 of 93 (6.5%) tumors negative for both the markers. Eleven tumors were CDX-2 positive (5 strong, 3 moderate, and 3 weak), all of which were also TTF-1 and napsin A positive and p40 negative. One CDX-2-positive tumor showed focal CK20 staining. Mutation studies for EGFR/K-ras/ALK were performed in four CDX-2-positive tumors and detected a K-ras mutation in one of them. CDX-2 positivity can be seen in a subset (12%) of lung adenocarcinoma. These tumors are CK7, TTF-1, and napsin A positive and p40 negative. Focal CK20 staining is only seen in rare cases. CDX-2 positivity should not be used as the only criteria to exclude lung origin.

Yaman B, Nart D, Ekren PK, et al.
Expression of p63, TTF-1 and Maspin in Non-Small Cell Lung Carcinoma and Their Effect on the Prognosis and Differential Diagnosis.
Turk Patoloji Derg. 2015; 31(3):163-74 [PubMed] Related Publications
OBJECTIVE: Lung cancer is still the leading cause of cancer mortality. Antiapoptotic genes and protease inhibitors play an important role in the development of lung cancer.
MATERIAL AND METHOD: p63, TTF-1 and maspin expression and their role in the differential diagnosis, overall survival, progression-free survival and other clinicopathological characteristics of the patients were investigated in 80 surgically-resected non-small cell lung carcinomas.
RESULTS: The maximal tumor diameter range was 1.5-11 cm (mean: 4.06±1.8 cm). Forty-five (56.3%) tumors were adenocarcinoma, 23 (28.8%) squamous cell carcinoma, four (5%) large cell carcinoma, six (7.5%) large cell neuroendocrine carcinoma, one (1.2%) sarcomatoid carcinoma while one was (1.2%) both adenocarcinoma and squamous cell carcinoma. The patients with advanced TNM stage and a tumor diameter more than 3 cm had markedly poor survival. Immunohistochemically, p63 staining was present in 87.5% of squamous cell carcinomas, 4.3% of adenocarcinomas, 25% of large cell carcinomas, and 16.7% of large cell neuroendocrine carcinomas. Similarly, maspin was positive in 66.7% of squamous cell carcinomas and 17.4% of adenocarcinomas. The TTF-1 staining rate was higher in adenocarcinomas (84.8%). There was no immunoreactivity in squamous cell carcinomas (p < 0.001). We found that p63 and TTF-1 had no significant effect on survival in either tumor group (p > 0.05) while maspin has a negative prognostic effect in adenocarcinoma (p=0.048).
CONCLUSION: This study suggests that p63 and TTF-1 are reliable markers in non-small cell lung carcinoma and can be used in differential diagnosis. Maspin has been identified as a prognostic marker in adenocarcinoma. However, more studies are required to elucidate the significance of maspin.

Batista FA, Ward LS, Marcello MA, et al.
Gene expression of thyroid-specific transcription factors may help diagnose thyroid lesions but are not determinants of tumor progression.
J Endocrinol Invest. 2016; 39(4):423-9 [PubMed] Related Publications
PURPOSE: The role of thyroid-specific transcription factors in thyroid malignancy is still poorly understood, so we investigate thyroid-specific transcription factors gene expression both in benign and in malignant thyroid nodules, aiming to study a possible clinical utility of these molecules.
METHODS: We quantified TTF-1, FOXE1 and PAX8 mRNA levels, relating their expression to diagnostic and prognostic features of thyroid tumors. RNA was extracted from 4 normal thyroid tissues, 101 malignant [99 papillary thyroid carcinomas (PTC) and 2 anaplastic thyroid carcinomas] and 99 benign thyroid lesion tissues [49 goiter and 50 follicular adenomas (FA)].
RESULTS: Levels of mRNA of both FOXE1 (P < 0.0001) and PAX8 (P < 0.0001) genes, but not TTF-1 (P = 0.7056), were higher in benign than in malignant thyroid lesions. FOXE1 was able to identify malignant nodules with 75.8 % sensitivity, 76.1 % specificity, 75.8 % positive predictive value, 76.1 % negative predictive value and 75.9 % accuracy. PAX8 was able to identify malignancy with 60.6 % sensitivity, 81.1 % specificity, 76.9 % positive predictive value, 66.4 % negative predictive value and 70.6 % accuracy. Both FOXE1 and PAX8 gene expression patterns were also able to differentiate FA from the follicular variant of PTC-FVPTC. However, the investigated gene expression was neither associated with any clinical feature of tumor aggressiveness nor associated with recurrence or survival.
CONCLUSIONS: We suggest that FOXE1 and PAX8 gene expression patterns may help to diagnose thyroid nodules, identifying malignancy and characterizing follicular-patterned thyroid lesions, but are not determinants of thyroid tumor progression.

Naderi S, Ghorra C, Haddad F, et al.
EGFR mutation status in Middle Eastern patients with non-squamous non-small cell lung carcinoma: A single institution experience.
Cancer Epidemiol. 2015; 39(6):1099-102 [PubMed] Related Publications
BACKGROUND: Epidermal growth factor receptor (EGFR) represents an important molecular target in the treatment of lung adenocarcinomas; many anti-EGFR therapies are approved as first line and second-line treatment in patients having metastatic lung adenocarcinomas. The occurrence of this mutation varies in terms of race; it is around 10% in Caucasians and can reach 30% in Asians. Its prevalence in our Middle Eastern region is not well known.
METHODS: Patients diagnosed with non-squamous non-small cell lung carcinomas between March 2013 and March 2015 were included. This study was conducted at Hôtel-Dieu de France University Hospital, a tertiary medical center in Lebanon. EFGR mutations were analyzed using real time PCR technique on the Rotor-Gene Q using Scorpions and ARMS technologies. The following data was collected: the patients' characteristics (age, gender, smoking status, stage), the samples' characteristics (histology subtype, TTF-1 and Napsin A immunostainings, the site and the adequacy and the type of the sample), and the mutational EGFR status (presence and type of mutation). These variables were analyzed using SPSS 20.
RESULTS: 201 patients were included. The mean age was 65.2 years [31-87]; 40.2% were females. 78.1% of the included patients were smokers or ex-smokers. 12.9% of patients had a localized disease, 17.4% a locally advanced disease and 69.7% a metastatic disease. Adenocarcinoma was the main histologic subtype found in 90.5% of patients, followed by large cell carcinoma (3.5%), adenosquamous carcinoma (3.0%) and non-small cell carcinoma not otherwise specified (3.0%). 11.9% of patients had an EGFR mutation: 48% of them presented a deletion on exon 19, 40.0% a L858R mutation on exon 21, 4.0% a G719X mutation in exon 18, 4.0% an insertion in exon 20, and 4% a T790M mutation in exon 20. The presence of an EGFR mutation was significantly associated with the female gender (two-third) (p<0.05) and the non-smoking status (two-third) (p<0.05).
CONCLUSIONS: The prevalence of EGFR mutation (11.9%) detected in our Lebanese population is similar to that observed in the Caucasian population. This mutation is also significantly more frequent in females and non-smokers.

Liu Y, Zhang G, Li H, et al.
Serum microRNA-365 in combination with its target gene TTF-1 as a non-invasive prognostic marker for non-small cell lung cancer.
Biomed Pharmacother. 2015; 75:185-90 [PubMed] Related Publications
BACKGROUND: MicroRNA (miR)-365 functions as a tumor suppressor in non-small cell lung cancer (NSCLC) cells by targeting thyroid transcription factor 1 (TTF-1).
AIM: To investigate miR-365 and TTF-1 mRNA expression in serum of NSCLC and their associations with patients' prognosis.
METHODS: MiR-365 and TTF-1 mRNA expression in 100 NSCLCs and 100 healthy control sera were detected by quantitative real-time PCR (qRT-PCR).
RESULTS: MiR-365 expression level was significantly lower in NSCLC serum samples than in healthy control serum samples (P<0.001), while TTF-1 mRNA expression level was significantly increased in NSCLC serum samples compared to healthy control serum samples (P<0.001). In addition, low miR-365 expression and high TTF-1 expression, alone or in combination, were all significantly associated with poor differentiation (P=0.008, 0.008 and 0.001, respectively), advanced TNM stage (P=0.001, 0.005 and <0.001 respectively) and positive lymph node metastasis (P=0.02, 0.02 and 0.01, respectively) of NSCLC patients. Notably, NSCLC patients with combined low miR-365 expression and high TTF-1 expression (miR-365-low/TTF-1-high) had shortest overall survival (P<0.001). Furthermore, multivariate analysis showed that miR-365 expression (P=0.01), TTF-1 expression (P=0.01), and combined expression of miR-365 and TTF-1 (miR-365/TTF-1, P=0.001) were all independent prognostic factors for overall survival in NSCLC patients.
CONCLUSIONS: Our data reveal that preoperative serum miR-365 and TTF-1 mRNA levels may be both effective indicators of tumor aggressiveness in human NSCLC. More interestingly, miR-365 and its target gene TTF-1 appear to be synergistic risk factors for the reduction in overall survival of patients with NSCLC.

Manzoni M, Roversi G, Di Bella C, et al.
Solid cell nests of the thyroid gland: morphological, immunohistochemical and genetic features.
Histopathology. 2016; 68(6):866-74 [PubMed] Related Publications
AIMS: The correct identification of solid cell nests (SCNs) is an important issue in thyroid pathology because of the spectrum of differential diagnoses of this type of lesion.
METHODS AND RESULTS: Ten cases of 295 consecutive thyroidectomies showed the presence of SCNs at histological examination. The identification of the exact SCN type required the distinction of the cystic and solid pattern; SCNs were usually composed of a mixture of main cells (MCs) and C-cells (CCs). The immunohistochemical calcitonin stain identified CCs easily, both inside SCNs and dispersed in islets at the periphery. For the characterization of MCs, we added the utility of p40 to p63. The use of thyroid transcription factor-1 (TTF-1) helped in their identification, as MCs did not react with this marker; the combination of TTF-1 and p40 or p63 IHC stains was useful for the characterization of cystic SCNs of both types 3 and 4. The negativity of mouse monoclonal mesothelioma antibody (HMBE-1) and a very low proliferative index (MIB-1) supported the diagnosis. [Correction added on 23 November 2015, after online publication: MIB-1 was incorrectly defined, the expanded form was deleted.] We discourage the use of galectin-3 (Gal-3) and cytokeratin-19 (CK-19), as they have an important overlap with papillary thyroid carcinoma. The complete absence of any B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations is an additional fundamental finding.
CONCLUSIONS: We reviewed the most relevant morphological and immunohistochemical features of SCNs and have provided a genetic analysis of the BRAF gene because of its expanding use in thyroid pathology.

Shih J, Bashir B, Gustafson KS, et al.
Cancer Signature Investigation: ERBB2 (HER2)-Activating Mutation and Amplification-Positive Breast Carcinoma Mimicking Lung Primary.
J Natl Compr Canc Netw. 2015; 13(8):947-52 [PubMed] Free Access to Full Article Related Publications
Next-generation sequencing of primary and metachronous metastatic cancer lesions may impact patient care. We present a case of relapsed metastatic breast cancer with a dominant pulmonary lesion originally identified as lung adenocarcinoma. A 72-year-old, never-smoker woman with a protracted cough was found to have a large lung mass and regional lymphadenopathy on a chest CT. Lung mass biopsy showed adenocarcinoma with focal TTF-1 (thyroid transcription factor 1) positivity, favoring a lung primary. In addition to stereotactic brain radiation for cerebral metastases, she was started on carboplatin/pemetrexed. As part of the workup, the tumor was analyzed by a 50-gene targeted mutation panel, which detected 3 somatic mutations: ERBB2 (HER2) D769H activating missense mutation, TP53 Y126 inactivating truncating mutation, and SMARCB1 R374Q missense mutation. Of note, the patient had a history of stage IIA triple-negative grade 3 invasive ductal carcinoma of the left breast 1.5 years ago and received neoadjuvant chemotherapy and adjuvant radiation, and underwent a lumpectomy. Further analysis of her primary breast tumor showed a mutational profile identical to that of the lung tumor. Fluorescence in situ hybridization revealed HER2 amplification in the lung tumor, with a HER2/CEP17 ratio of 3.9. The patient was diagnosed with recurrent HER2-positive metastatic breast carcinoma with a coexisting ERBB2 (HER2) activating mutation. Chemotherapy was adjusted to include dual HER2-targeted therapy containing trastuzumab and pertuzumab, resulting in an ongoing partial response. This case demonstrates that a unique genetic mutational profile can clarify whether a tumor represents a metastatic lesion or new malignancy when conventional morphological and immunohistochemical methods are indeterminate, and can directly impact treatment decisions.

Qing S, Zhou K, Liu X, et al.
Primary pulmonary adenoid cystic carcinoma: clinicopathological analyses of 12 cases.
Int J Clin Exp Pathol. 2015; 8(6):7619-26 [PubMed] Free Access to Full Article Related Publications
BACKGROUND AND OBJECTIVES: Adenoid cystic primary pulmonary carcinomas (adenoid cystic carcinomas or ACCs) are rare tumors, so we described the clinical and pathological features of these tumors and related these findings with diagnosis and prognosis of ACC, comparing our data to the existing literature.
METHODS: Clinical and pathological features of 12 ACC cases were observed and described. Immunohistochemical EnVision staining, fluorescent PCR detection, and FISH were used to characterize tumor samples and the literature was reviewed.
RESULTS: Of the 12 ACC cases (7 male; average 53.1 years-of-age; range 33-78 years), the chief presentation symptom was cough, followed by expectoration, gasping, and bloody sputum. Microscopically, histopathology revealed cribriform, tubular, or solid cords. CD117 was overexpressed in glandular epithelia in 9 cases and calcitonin and thyroid transcription factor-1 (TTF-1) were overexpressed in 4 cases. One case was positive for EML4 ALK gene rearrangement.
CONCLUSION: ACC is a low-grade malignant tumor with poor prognosis and high recurrence and metastases. TTF-1 expression indicates a primary tumor and CD117 expression is not significant to prognosis.

Chatziandreou I, Tsioli P, Sakellariou S, et al.
Comprehensive Molecular Analysis of NSCLC; Clinicopathological Associations.
PLoS One. 2015; 10(7):e0133859 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Selection of NSCLC patients for targeted therapy is currently based upon the presence of sensitizing mutations in EGFR and EML4/ALK translocations. The heterogeneity of molecular alterations in lung cancer has led to the ongoing discovery of potential biomarkers and targets in order to improve survival.
AIM: This study aimed to detect alterations in EGFR, KRAS, BRAF, PIK3CA, MET-gene copy number and ALK rearrangements in a large cohort of 956 NSCLC patients of Hellenic origin using highly sensitive techniques and correlations with clinicopathological characteristics.
RESULTS: Mutations were detected in EGFR 10.6% (101 out of 956 samples), KRAS 26.5% (191 out of 720 samples), BRAF 2.5% (12 out of 471 samples), PIK3CA 3.8% (7 out of 184 samples), MET gene amplification was detected in 18% (31 out of 170) and ALK rearrangements in 3.7% (4 out of 107 samples). EGFR mutations were detected in exon 19 (61.4% of mutant cases), exon 21 p.Leu858Arg (19.8%), exon 20 (15.8%), exon 18 (2.9%) and were correlated with gender histology, smoking status and TTF1 staining. p.Thr790Met mutant cases (3.9%) displayed concurrent mutations in exons 19 or 21. Negative TTF-1 staining showed strong negative predictive value for the presence of EGFR mutations. KRAS mutations were associated with histology, the most common mutation being p.Gly12Cys (38%).
DISCUSSION: In conclusion, only 89 patients were eligible for EGFR -TKIs and ALK inhibitors therapy, whereas 257 patients showed other alterations, highlighting the necessity for a detailed molecular profiling potentially leading to more efficient individualized therapies for NSCLC patients.

Poret N, Fu Q, Guihard S, et al.
CD38 in Hairy Cell Leukemia Is a Marker of Poor Prognosis and a New Target for Therapy.
Cancer Res. 2015; 75(18):3902-11 [PubMed] Related Publications
Hairy cell leukemia (HCL) is characterized by underexpression of the intracellular signaling molecule RhoH. Reconstitution of RhoH expression limits HCL pathogenesis in a mouse model, indicating this could represent a new therapeutic strategy. However, while RhoH reconstitution is theoretically possible as a therapy, it is technically immensely challenging as an appropriately functional RhoH protein needs to be specifically targeted. Because of this problem, we sought to identify druggable proteins on the HCL surface that were dependent upon RhoH underexpression. One such protein was identified as CD38. Analysis of 51 HCL patients demonstrated that 18 were CD38-positive. Interrogation of the clinical record of 23 relapsed HCL patients demonstrated those that were CD38-positive had a mean time to salvage therapy 71 months shorter than patients who were CD38-negative. Knockout of the CD38 gene in HCL cells increased apoptosis, inhibited adherence to endothelial monolayers, and compromised ability to produce tumors in vivo. Furthermore, an anti-CD38 antibody proved effective against pre-existing HCL tumors. Taken together, our data indicate that CD38 expression in HCL drives poor prognosis by promoting survival and heterotypic adhesion. Our data also indicate that CD38-positive HCL patients might benefit from treatments based on CD38 targeting.

Li S, Tian Y, Zhao Y, et al.
pHLIP-mediated targeting of truncated tissue factor to tumor vessels causes vascular occlusion and impairs tumor growth.
Oncotarget. 2015; 6(27):23523-32 [PubMed] Free Access to Full Article Related Publications
Occluding tumor blood supply by delivering the extracellular domain of coagulation-inducing protein tissue factor (truncated tissue factor, tTF) to tumor vasculature has enormous potential to eliminate solid tumors. Yet few of the delivery technologies are moved into clinical practice due to their non-specific tissue biodistribution and rapid clearance by the reticuloendothelial system. Here we introduced a novel tTF delivery method by generating a fusion protein (tTF-pHLIP) consisting of tTF fused with a peptide with a low pH-induced transmembrane structure (pHLIP). This protein targets the acidic tumor vascular endothelium and effectively induces local blood coagulation. tTF-pHLIP, wherein pHLIP is cleverly designed to mimic the natural tissue factor transmembrane domain, triggered thrombogenic activity of the tTF by locating it to the endothelial cell surface, as demonstrated by coagulation assays and confocal microscopy. Systemic administration of tTF-pHLIP into tumor-bearing mice selectively induced thrombotic occlusion of tumor vessels, reducing tumor perfusion and impairing tumor growth without overt side effects. Our work introduces a promising strategy for using tTF as an anti-cancer drug, which has great potential value for clinical applications.

Karlsson A, Brunnström H, Lindquist KE, et al.
Mutational and gene fusion analyses of primary large cell and large cell neuroendocrine lung cancer.
Oncotarget. 2015; 6(26):22028-37 [PubMed] Free Access to Full Article Related Publications
Large cell carcinoma with or without neuroendocrine features (LCNEC and LC, respectively) constitutes 3-9% of non-small cell lung cancer but is poorly characterized at the molecular level. Herein we analyzed 41 LC and 32 LCNEC (including 15 previously reported cases) tumors using massive parallel sequencing for mutations in 26 cancer-related genes and gene fusions in ALK, RET, and ROS1. LC patients were additionally subdivided into three immunohistochemistry groups based on positive expression of TTF-1/Napsin A (adenocarcinoma-like, n = 24; 59%), CK5/P40 (squamous-like, n = 5; 12%), or no marker expression (marker-negative, n = 12; 29%). Most common alterations were TP53 (83%), KRAS (22%), MET (12%) mutations in LCs, and TP53 (88%), STK11 (16%), and PTEN (13%) mutations in LCNECs. In general, LCs showed more oncogene mutations compared to LCNECs. Immunomarker stratification of LC revealed oncogene mutations in 63% of adenocarcinoma-like cases, but only in 17% of marker-negative cases. Moreover, marker-negative LCs were associated with inferior overall survival compared with adenocarcinoma-like tumors (p = 0.007). No ALK, RET or ROS1 fusions were detected in LCs or LCNECs. Together, our molecular analyses support that LC and LCNEC tumors follow different tumorigenic paths and that LC may be stratified into molecular subgroups with potential implications for diagnosis, prognostics, and therapy decisions.

Choueiri MB, Shen JP, Gross AM, et al.
ERCC1 and TS Expression as Prognostic and Predictive Biomarkers in Metastatic Colon Cancer.
PLoS One. 2015; 10(6):e0126898 [PubMed] Free Access to Full Article Related Publications
In patients with metastatic colon cancer, response to first line chemotherapy is a strong predictor of overall survival (OS). Currently, oncologists lack diagnostic tests to determine which chemotherapy regimen offers the greatest chance for response in an individual patient. Here we present the results of gene expression analysis for two genes, ERCC1 and TS, measured with the commercially available ResponseDX: Colon assay (Response Genetics, Los Angeles, CA) in 41 patients with de novo metastatic colon cancer diagnosed between July 2008 and August 2013 at the University of California, San Diego. In addition ERCC1 and TS expression levels as determined by RNAseq and survival data for patients in TCGA were downloaded from the TCGA data portal. We found that patients with low expression of ERCC1 (n = 33) had significantly longer median OS (36.0 vs. 10.1 mo, HR 0.29, 95% CI .095 to .84, log-rank p = 9.0x10-6) and median time to treatment to failure (TTF) following first line chemotherapy (14.1 vs. 2.4 mo, HR 0.17, 95% CI 0.048 to 0.58, log-rank p = 5.3x10-4) relative to those with high expression (n = 4). After accounting for the covariates age, sex, tumor grade and ECOG performance status in a Cox proportional hazard model the association of low ERCC1 with longer OS (HR 0.18, 95% CI 0.14 to 0.26, p = 0.0448) and TTF (HR 0.16, 95% CI 0.14 to 0.21, p = 0.0053) remained significant. Patients with low TS expression (n = 29) had significantly longer median OS (36.0 vs. 14.8 mo, HR 0.25, 95% CI 0.074 to 0.82, log-rank p = 0.022) relative to those with high expression (n = 12). The combined low expression of ERCC1/TS was predictive of response in patients treated with FOLFOX (40% vs. 91%, RR 2.3, Fisher's exact test p = 0.03, n = 27), but not with FOLFIRI (71% vs. 71%, RR 1.0, Fisher's exact test p = 1, n = 14). Overall, these findings suggest that measurement of ERCC1 and TS expression has potential clinical utility in managing patients with metastatic colorectal cancer.

Sun R, Liu Z, Ma G, et al.
Associations of deregulation of mir-365 and its target mRNA TTF-1 and survival in patients with NSCLC.
Int J Clin Exp Pathol. 2015; 8(3):2392-9 [PubMed] Free Access to Full Article Related Publications
microRNA (mir)-365 exerts tumor suppressor function by targeting thyroid transcription factor-1 (TTF-1) in lung cancer cells. The purpose of the present study was to assess mir-365 and its target mRNA TTF-1 in lung cancer and their correlations with patients' survival. Quantitative real-time PCR was used to examine the expression levels of mir-365 and TTF-1 in tumor tissue and its adjacent noncancerous tissue of 126 patients with non-small cell lung cancer (NSCLC). Our results showed that mir-365 was significantly decreased in tumor tissue than that in normal tissue (P=0.006), however, TTF-1 was significantly increased in tumor tissue than in normal tissue (P<0.001). Besides, significant correlations between decreased mir-365 and advanced tumor-node-metastasis (TNM) stage (P=0.001) and regional lymph node involvement (P=0.037) was observed. The similar result was also found between increased TTF-1 and TNM stage (P=0.003). Furthermore, mir-365 downregulation or TTF-1 upregulation were associated with poor outcome of patients than mir-365 upregulation or TTF-1 downregulation (for mir-365: P<0.001; for TTF-1: P=0.002). Of note, combination of decreased mir-365 and increased TTF-1 had worst overall survival (P<0.001). In conclusion, aberrant expression of mir-365/TTF-1 may be involved in the tumor development in patients with NSCLC. Moreover, mir-365 and TTF-1 could jointly predict the prognosis of patients and their combination may serve as a biomarker to predict risk of poor survival in NSCLC patients. Mir-365/TTF-1 might serve as a potential therapeutic target for clinical treatment of NSCLC.

Sato S, Motoi N, Hiramatsu M, et al.
Pulmonary adenocarcinoma in situ: analyses of a large series with reference to smoking, driver mutations, and receptor tyrosine kinase pathway activation.
Am J Surg Pathol. 2015; 39(7):912-21 [PubMed] Related Publications
Lung adenocarcinomas in situ (AISs) often occur in individuals who have never smoked, although smoking is one of the main causes of lung cancer. To characterize AIS and, in particular, determine how AIS might be related to smoking, we collected a large number of AIS cases and examined clinicopathologic features, EGFR and KRAS mutation status, and activation status of receptor tyrosine kinase downstream signal pathways, including pAkt, pERK, and pStat3, using immunohistochemistry. We identified 110 AISs (36 smokers and 74 nonsmokers) among 1549 adenocarcinomas resected surgically during 1995 to 2010. Between the AIS of smokers and nonsmokers, only the sex ratio was significantly different; all the other clinicopathologic factors including TTF-1 and driver mutations were not significantly different: EGFR and KRAS mutation rates (smokers:nonsmokers) were 61:58 (%) (P=0.7) and 6.1:1.4 (%) (P=0.2), respectively, whereas, in invasive adenocarcinomas, the rates were 41:69 (%) (P<0.001) and 9.4:2.3 (%) (P<0.04), respectively. For pAkt and pERK, around 40% to 50% of AISs were positive, and for pStat3, >80% were positive, with no significant differences between smokers and nonsmokers with AIS. Mucinous AIS (n=8) rarely harbored KRAS mutations and expressed significantly less pStat3 (P<0.001) than nonmucinous AIS. Taken together, AIS occurs predominantly in female individuals and nonsmokers. However, characteristics of AIS arising in smokers and nonsmokers were similar in terms of cell lineage, driver mutations, and receptor tyrosine kinase pathway activation. Our results suggest that smoking is not a major cause of AIS. Rather, smoking may play a role in progression of AIS to invasive adenocarcinoma with AIS features.

Collaud S, Tischler V, Atanassoff A, et al.
Lung neuroendocrine tumors: correlation of ubiquitinylation and sumoylation with nucleo-cytosolic partitioning of PTEN.
BMC Cancer. 2015; 15:74 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The tumor suppressor phosphatase and tensin homolog (PTEN) is a pleiotropic enzyme, inhibiting phosphatidyl-inositol-3 kinase (PI3K) signaling in the cytosol and stabilizing the genome in the nucleus. Nucleo-cytosolic partitioning is dependent on the post-translational modifications ubiquitinylation and sumoylation. This cellular compartmentalization of PTEN was investigated in lung neuroendocrine tumors (lung NET).
METHODS: Tumor tissues from 192 lung NET patients (surgical specimens = 183, autopsies = 9) were investigated on tissue microarrays. PTEN was H-scored by two investigators in nucleus and cytosol using the monoclonal antibody 6H2.1. Results were correlated with immunoreactivity for USP7 (herpes virus-associated ubiquitin-specific protease 7) and SUMO2/3 (small ubiquitin-related modifier protein 2/3) as well as PTEN and p53 FISH gene status. Clinico-pathologic data including overall survival, proliferation rate and diagnostic markers (synaptophysin, chromogranin A, Mib-1, TTF-1) were recorded.
RESULTS: The multicentre cohort included 58 typical carcinoids (TC), 42 atypical carcinoids (AC), 32 large cell neuroendocrine carcinomas (LCNEC) and 60 small cell lung carcinomas (SCLC). Carcinoids were smaller in size and had higher synaptophysin and chromogranin A, but lower TTF-1 expressions. Patients with carcinoids were predominantly female and 10 years younger than patients with LCNEC/SCLC. In comparison to the carcinoids, LCNEC/SCLC tumors presented a stronger loss of nuclear and cytosolic PTEN associated with a loss of PTEN and p53. Concomitantly, a loss of nuclear USP7 but increase of nuclear and cytosolic SUMO2/3 was found. Loss of nuclear and cytosolic PTEN, loss of nuclear USP7 and increase of cytosolic SUMO2/3 thus correlated with poor survival. Among carcinoids, loss of cytosolic PTEN was predominantly found in TTF1-negative larger tumors of male patients. Among SCLC, loss of both cytosolic and nuclear PTEN but not proliferation rate or tumor size delineated a subgroup with poorer survival (all p-values <0.05).
CONCLUSIONS: Cellular ubiquitinylation and sumoylation likely influence the functional PTEN loss in high grade lung NET. Both nuclear and cytosolic PTEN immunoreactivity should be considered for correlation with clinico-pathologic parameters.

Suzuki M, Yazawa T, Ota S, et al.
High-grade fetal adenocarcinoma of the lung is a tumour with a fetal phenotype that shows diverse differentiation, including high-grade neuroendocrine carcinoma: a clinicopathological, immunohistochemical and mutational study of 20 cases.
Histopathology. 2015; 67(6):806-16 [PubMed] Related Publications
AIMS: High-grade fetal adenocarcinoma (H-FLAC) is a rare variant of pulmonary adenocarcinoma; this study aims to elucidate its clinicopathological features and genetic abnormalities.
METHODS AND RESULTS: Clinicopathological, immunohistochemical and mutational analyses were performed on 20 surgically resected lung cancers that showed H-FLAC histology in various proportions. These tumours predominantly occurred in elderly males and in 10 patients who were heavy smokers. Four cases were pure H-FLAC, and 16 cases were mixed H-FLAC, which were found to be combined with conventional-type adenocarcinoma (15 cases), large-cell neuroendocrine carcinoma (three cases), small-cell carcinoma (one case), enteric adenocarcinoma (two cases), choriocarcinoma (two cases), and a solid-clear cell pattern (seven cases). The fetal phenotype and diverse differentiation were supported by the immunoexpression of α-fetoprotein (95%), thyroid transcription factor-1 (TTF-1) (50%), neuroendocrine markers (30-45%), proneural markers (50-69%), and CDX2 (40%). Except for TTF-1 expression (pure H-FLACs, 0%; mixed H-FLACs, 63%), there were no significant differences in histological or immunohistochemical findings between pure and mixed H-FLACs. EGFR, KRAS, BRAF and PIK3CA mutations were identified in 20%, 0%, 0% and 7% of the tumours, respectively.
CONCLUSIONS: Lung adenocarcinomas with H-FLAC features possess the potential for multidirectional differentiation, and are not strongly associated with known major driver gene mutations.

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