Gene Summary

Gene:TFG; TRK-fused gene
Aliases: TF6, HMSNP, SPG57, TRKT3
Summary:There are several documented fusion oncoproteins encoded partially by this gene. This gene also participates in several oncogenic rearrangements resulting in anaplastic lymphoma and mixoid chondrosarcoma, and may play a role in the NF-kappaB pathway. Multiple transcript variants have been found for this gene. [provided by RefSeq, Sep 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:protein TFG
Source:NCBIAccessed: 17 August, 2015


What does this gene/protein do?
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Cancer Overview

Research Indicators

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

Literature Analysis

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Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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: TFG (cancer-related)

Starska K, Forma E, Jóźwiak P, et al.
Gene and protein expression of glucose transporter 1 and glucose transporter 3 in human laryngeal cancer-the relationship with regulatory hypoxia-inducible factor-1α expression, tumor invasiveness, and patient prognosis.
Tumour Biol. 2015; 36(4):2309-21 [PubMed] Free Access to Full Article Related Publications
Increased glucose uptake mediated by glucose transporters and reliance on glycolysis are common features of malignant cells. Hypoxia-inducible factor-1α supports the adaptation of hypoxic cells by inducing genes related to glucose metabolism. The contribution of glucose transporter (GLUT) and hypoxia-inducible factor-1α (HIF-1α) activity to tumor behavior and their prognostic value in head and neck cancers remains unclear. The aim of this study was to examine the predictive value of GLUT1, GLUT3, and HIF-1α messenger RNA (mRNA)/protein expression as markers of tumor aggressiveness and prognosis in laryngeal cancer. The level of hypoxia/metabolic marker genes was determined in 106 squamous cell laryngeal cancer (SCC) and 73 noncancerous matched mucosa (NCM) controls using quantitative real-time PCR. The related protein levels were analyzed by Western blot. Positive expression of SLC2A1, SLC2A3, and HIF-1α genes was noted in 83.9, 82.1, and 71.7% of SCC specimens and in 34.4, 59.4, and 62.5% of laryngeal cancer samples. Higher levels of mRNA/protein for GLUT1 and HIF-1α were noted in SCC compared to NCM (p < 0.05). SLC2A1 was found to have a positive relationship with grade, tumor front grading (TFG) score, and depth and mode of invasion (p < 0.05). SLC2A3 was related to grade and invasion type (p < 0.05). There were also relationships of HIF-1α with pTNM, TFG scale, invasion depth and mode, tumor recurrences, and overall survival (p < 0.05). In addition, more advanced tumors were found to be more likely to demonstrate positive expression of these proteins. In conclusion, the hypoxia/metabolic markers studied could be used as molecular markers of tumor invasiveness in laryngeal cancer.

McFadden DG, Dias-Santagata D, Sadow PM, et al.
Identification of oncogenic mutations and gene fusions in the follicular variant of papillary thyroid carcinoma.
J Clin Endocrinol Metab. 2014; 99(11):E2457-62 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: The diagnosis of the follicular variant of papillary thyroid carcinoma (FVPTC) is increasingly common. Recent studies have suggested that FVPTC is heterogeneous and comprises multiple tumor types with distinct biological behaviors and underlying genetics.
OBJECTIVES: The purpose of this work was to identify the prevalence of mutations and gene fusions in known oncogenes in a panel representative of the common spectrum of FVPTC diagnosed at an academic medical center and correlate the clinical and pathological features obtained at the initial diagnosis with the tumor genotype.
MATERIALS AND METHODS: We performed SNaPshot genotyping on a panel of 129 FVPTCs of ≥1 cm for 90 point mutations or small deletions in known oncogenes and tumor suppressors and identified gene fusions using an anchored multiplex PCR assay targeting a panel of rearranged oncogenes.
RESULTS: We identified a mutation or gene fusion in 70% (89 of 127) of cases. Mutations targeting the RAS family of oncogenes were the most frequently observed class of alterations, present in 36% (46 of 127) of cases, followed by BRAF mutation, present in 30% (38 of 127). We also detected oncogenic rearrangements not previously associated with FVPTC, including TFG-ALK and CREB3L2-PPARγ. BRAF mutation was significantly associated with unencapsulated tumor status.
CONCLUSIONS: These data support the hypothesis that FVPTC is composed of distinct biological entities, with one class being identified by BRAF mutation and support the use of clinical genotyping assays that detect a diverse array of rearrangements involving ALK and PPARγ. Additional studies are necessary to identify genetic drivers in the 30% of FVPTCs with no known oncogenic alteration and to better predict behavior in tumors with known genotypes.

Broehm CJ, Wu J, Gullapalli RR, Bocklage T
Extraskeletal myxoid chondrosarcoma with a t(9;16)(q22;p11.2) resulting in a NR4A3-FUS fusion.
Cancer Genet. 2014; 207(6):276-80 [PubMed] Related Publications
Extraskeletal myxoid chondrosarcoma (EMC) is a rare neoplasm characterized by rearrangement of NR4A3. A t(9;22)(q22;q12), creating a fusion protein of EWSR1 and NR4A3, has been reported as a unique, recurring translocation in most cases. Reported variant translocations have resulted in fusion of NR4A3 with three other genes: TAF15, TCF12, and TFG. We report a case of EMC in a 59-year-old man who presented with a 6-month history of an enlarging mass in the proximal right thigh. The karyotype of fresh tissue from tumor taken at incisional biopsy revealed a t(9;16)(q22;p11.2). There was no evidence of an EWSR1 rearrangement by dual-color break-apart fluorescence in situ hybridization (FISH). Dual-color FISH probes revealed fusion of NR4A3 and FUS, a member of the TET family of genes, which includes EWSR1 and TAF15. Break-apart FISH probe results confirmed rearrangement of FUS. These findings show that a fusion product of FUS and NR4A3 may be an additional pathway to development of EMC.

Starska K, Krześlak A, Forma E, et al.
Genetic polymorphism of metallothionein 2A and risk of laryngeal cancer in a Polish population.
Med Oncol. 2014; 31(7):75 [PubMed] Related Publications
Metallothioneins are intracellular regulators of many biological mechanisms including differentiation, proliferation, angiogenesis and invasion, which are crucial processes in carcinogenesis. This study examines the association between three single-nucleotide polymorphisms at loci -5 A/G (rs28366003) and -209 A/G (rs1610216) in the core promoter region and at locus +838 C/G (rs10636) in 3'UTR region of the metallothionein 2A (MT2A) gene with squamous cell laryngeal cancer (SCLC) risk, as well as with tumor invasiveness according to tumor front grading (TFG). Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism technique in 323 genetically unrelated individuals with SCLC and 418 randomly selected healthy volunteers. Only one SNP (rs28366003) was significantly related to laryngeal cancer in the study population. Compared with homozygous common allele carriers, heterozygous and homozygous for the G variant had significantly increased risk of SCLC [adjusted odds ratio (OR) = 2.90, 95 % confidence interval (CI) 1.53-5.21, p dominant < 0.001]. The A/G allele carriers at rs28366003 MT2A were at higher risk of SCLC development (OR = 2.63, 95 % CI 1.41-2.85, p < 0.001]. There was a significant association between the rs28366003 and stage and TFG classification. Most carriers of minor allele had a higher stage (OR = 2.76, 95 % CI 1.11-7.52, p = 0.03), increased cancer aggressiveness, as defined by a higher total TFG score (>18 points) (OR = 3.76, 95 % CI 1.15-12.56, p = 0.03) and diffuse tumor growth (OR = 5.86, 95 % Cl 0.72-44.79, p = 0.08). The results of this study raise a possibility that a genetic variation of MT2A may be implicated in the etiology of laryngeal cancer in a Polish population.

Agaram NP, Zhang L, Sung YS, et al.
Extraskeletal myxoid chondrosarcoma with non-EWSR1-NR4A3 variant fusions correlate with rhabdoid phenotype and high-grade morphology.
Hum Pathol. 2014; 45(5):1084-91 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Extraskeletal myxoid chondrosarcomas (EMC) are rare soft tissue sarcomas with distinctive histology and uncertain histogenesis, characterized by Ewing sarcoma breakpoint region 1-nuclear receptor subfamily 4, group A, member 3 (EWSR1-NR4A3) fusion in 75% of the cases. A smaller proportion of cases show NR4A3 fused to other gene partners including TATA binding protein-associated factor 15 (TAF15), transcription factor 12 (TCF12), and TRK-fused gene (TFG). The impact of various gene fusions on morphology and outcome has not been previously evaluated. We investigated 26 consecutive EMCs and correlated the genetic findings with morphology and clinical outcome. There were 5 females and 21 males (median age, 49.5 years). Mean size of the tumors was 11 cm. Fluorescence in situ hybridization analysis showed EWSR1-NR4A3 gene fusion in 16 cases (62%), TAF15-NR4A3 gene fusion in 7 cases (27%), and TCF12-NR4A3 gene fusion in 1 case (4%). Two cases showed only NR4A3 gene rearrangements. Morphologically, most EWSR1-rearranged tumors (10/16) showed low cellularity, minimal cytologic atypia, and low mitotic counts. In contrast, 80% of EMCs with variant (non-EWSR1) NR4A3 gene fusions (TAF15, TCF12) had high-grade morphology with increased cellularity, proliferation, and cytologic atypia, showing a plasmacytoid/rhabdoid morphology in half the cases. Follow-up showed that only 1 of 16 patients with EWSR1-rearranged tumors died of disease, in contrast to 3 (43%) of 7 TAF15-rearranged tumors. In conclusion, EMCs with variant NR4A3 gene fusions show a higher incidence of rhabdoid phenotype, high-grade morphology, and a more aggressive outcome compared with the EWSR1-NR4A3 positive tumors. Furthermore, fluorescence in situ hybridization assay for NR4A3, along with EWSR1, may be an additional ancillary test to confirm diagnosis of EMCs.

Chen Y, Tseng SH
Targeting tropomyosin-receptor kinase fused gene in cancer.
Anticancer Res. 2014; 34(4):1595-600 [PubMed] Related Publications
Tropomyosin-receptor kinase fused gene (TRK-fused gene, TFG) encodes a protein which is a conserved regulator of protein secretion that localizes in the endoplasmic reticulum exit sites and controls the export of materials from the endoplasmic reticulum. It is important for intracellular trafficking of protein secretion. TFG belongs to the systems which control cell size, and is involved in regulatory mechanisms of apoptosis and cell proliferation. The TFG fusion proteins have been found to play a role in oncogenesis, with the activity of TFG fusion proteins promoting tumor development. In addition, TFG alone has been demonstrated to function like an oncoprotein; however, there are contradictory data suggesting TFG might act as a tumor suppressor. In this article, we will review the functions and regulation of TFG, the TFG fusion proteins, and the role of TFG in tumorigenesis. Finally, the potential of targeting TFG in cancer treatment is discussed.

Hsu TI, Lin SC, Lu PS, et al.
MMP7-mediated cleavage of nucleolin at Asp255 induces MMP9 expression to promote tumor malignancy.
Oncogene. 2015; 34(7):826-37 [PubMed] Related Publications
Nucleolin (NCL) participates in DNA transcription, ribosomal biogenesis and the regulation of RNA stability. However, the contribution of NCL to tumor development is still not clear. Herein, we found that NCL expression correlated with poor prognosis in lung cancer patients. Overexpressed NCL was predominantly cleaved to C-terminal truncated NCL (TNCL). In lung cancer formation, activation of the epidermal growth factor receptor pathway induced NCL expression, and also the expression of matrix metalloproteinase (MMP) 7, which then cleaved NCL at Asp255 to generate TNCL of 55 kDa. TNCL increased the expression of several oncogenes, including MMP9, anaplastic lymphoma kinase (ALK), HIF1a and CBLB, and decreased the expression of tumor suppressors including BRD4, PCM1, TFG and KLF6 by modulating mRNA stability through binding to the 3'-untranslated regions of their transcripts, thus ultimately enhancing metastasis activity. In conclusion, this study identified a novel role of the cleavage form of NCL generated by MMP7 in stabilizing MMP9 mRNA. We also provide a new insight that MMP7 not only cleaves the extracellular matrix to promote tumor invasion but also cleaves NCL, which augment oncogenesis. Blocking NCL cleavage may provide a useful new strategy for lung cancer therapy.

Benini S, Cocchi S, Gamberi G, et al.
Diagnostic utility of molecular investigation in extraskeletal myxoid chondrosarcoma.
J Mol Diagn. 2014; 16(3):314-23 [PubMed] Related Publications
Extraskeletal myxoid chondrosarcoma is characterized by the reciprocal chromosomal translocation t(9;22) and the resultant fused gene EWS RNA-binding protein 1 and nuclear receptor subfamily 4, group A, member 3 (EWSR1-NR4A3). A second cytogenetic rearrangement t(9;17) involves the genes NR4A3 and TAF 15 RNA polymerase II, TATA box binding protein (TBP)-associated factor (TAF15). Less frequent fusion transcript variants of the NR4A3 gene, transcription factor 12 (TCF12)-NR4A3 and TRK-fused gene (TFG)-NR4A3, are associated with t(9;15) and t(9;3) respectively. The samples from 42 patients with extraskeletal myxoid chondrosarcoma were examined for the presence of EWSR1-NR4A3, TAF15-NR4A3, TCF12-NR4A3, and TFG-NR4A3 fusion transcripts by using RT-PCR. Fluorescence in situ hybridization was performed to analyze the status of EWSR1 and NR4A3 genes. The fusion transcripts were detected in 34 of 42 samples (81%); the presence of an EWSR1 or NR4A3 gene rearrangements were detected in 8 of 42 samples (19%) which had tested negative for all fusion transcripts detected by RT-PCR. Of the 34 samples evaluable for fusion transcripts, 23 yielded positive results for EWSR1-NR4A3, 10 for TAF15-NR4A3, and 1 for TCF12-NR4A3. The combination of RT-PCR and fluorescence in situ hybridization on frozen and paraffin-embedded tissue is a sensitive and specific method for molecular detection of recurrent translocations and is an important ancillary method to establish the diagnosis of extraskeletal myxoid chondrosarcoma.

Lyons AJ, Nixon I, Papadopoulou D, Crichton S
Can we predict which patients are likely to develop severe complications following reconstruction for osteoradionecrosis?
Br J Oral Maxillofac Surg. 2013; 51(8):707-13 [PubMed] Related Publications
High morbidity has been reported for free vascularised reconstruction for osteoradionecrosis (ORN) and there are no apparent risk factors. A single nucleotide polymorphism in the transforming growth factor beta 1 gene (TGF-β1) has been implicated in the cause of ORN and may also predict these complications. We studied a series of 30 consecutive patients who had had reconstruction for severe ORN with free tissue transfer in relation to their outcomes and complications for a number of risk factors including TFG-β1 genotype, age, sex, comorbidities, site and stage of tumour, type of initial operation, and dose of radiotherapy or chemoradiotherapy. Two patients died and 2 flaps failed. Using the Clavien-Dindo classification, 16 patients developed grade III complications and 6 grade II. Median (IQR) duration of inpatient stay was 19.5 (12-25) days and the median (IQR) duration of outpatient treatment was 6 (4-11) weeks. No specific risk factors for postoperative complications were identified. In view of the severity and unpredictability of the complications, careful preoperative counselling of patients is essential.

Lim B, Kim AY, Jun HJ, Kim J
A TFG-TEC nuclear localization mutant forms complexes with the wild-type TFG-TEC oncoprotein and suppresses its activity.
Biochem J. 2013; 456(3):361-72 [PubMed] Related Publications
Human EMCs (extraskeletal myxoid chondrosarcomas) are soft tissue tumours characterized by specific chromosomal abnormalities. Recently, a proportion of EMCs were found to harbour a characteristic translocation, t(3;9)(q11-12;q22), involving the TFG (TRK-fused gene) at 3q11-12 and the TEC (translocated in extraskeletal chondrosarcoma) gene at 9q22. The present study used both in vitro and in vivo systems to show that the TFG-TEC protein self-associates, and that this is dependent upon the CC (coiled-coil) domain (amino acids 97-124), the AF1 (activation function 1) domain (amino acids 275-562) and the DBD (DNA-binding domain) (amino acids 563-655). The TFG-TEC protein also associated with a mutant NLS-TFG-TEC (AAAA) protein, which harbours mutations in the NLS (nuclear localization signal). Subcellular localization assays showed that the NLS mutant TFG-TEC (AAAA) protein interfered with the nuclear localization of wild-type TFG-TEC. Most importantly, the mutant protein inhibited TFG-TEC-mediated transcriptional activation in vivo. Thus mutations in the TFG-TEC NLS yield a dominant-negative protein. These results show that the biological functions of the TFG-TEC oncogene can be modulated by a dominant-negative mutant.

Lim B, Jun HJ, Kim AY, et al.
The TFG-TEC fusion gene created by the t(3;9) translocation in human extraskeletal myxoid chondrosarcomas encodes a more potent transcriptional activator than TEC.
Carcinogenesis. 2012; 33(8):1450-8 [PubMed] Related Publications
The t(3;9)(q11-q12;q22) translocation associated with human extraskeletal myxoid chondrosarcomas results in a chimeric molecule in which the N-terminal domain (NTD) of the TFG (TRK-fused gene) is fused to the TEC (Translocated in Extraskeletal Chondrosarcoma) gene. Little is known about the biological function of TFG-TEC. Because the NTDs of TFG-TEC and TEC are structurally different, and the TFG itself is a cytoplasmic protein, the functional consequences of this fusion in extraskeletal myxoid chondrosarcomas were examined. The results showed that the chimeric gene encoded a nuclear protein that bound DNA with the same sequence specificity as the parental TEC protein. Comparison of the transactivation properties of TFG-TEC and TEC indicated that the former has higher transactivation activity for a known target reporter containing TEC-binding sites. Additional reporter assays for TFG (NTD) showed that the TGF (NTD) of TFG-TEC induced a 12-fold increase in the activation of luciferase from a reporter plasmid containing GAL4 binding sites when fused to the DNA-binding domain of GAL4, indicating that the TFG (NTD) of the TFG-TEC protein has intrinsic transcriptional activation properties. Finally, deletion analysis of the functional domains of TFG (NTD) indicated that the PB1 (Phox and Bem1p) and SPYGQ-rich region of TFG (NTD) were capable of activating transcription and that full integrity of TFG (NTD) was necessary for full transactivation. These results suggest that the oncogenic effect of the t(3;9) translocation may be due to the TFG-TEC chimeric protein and that fusion of the TFG (NTD) to the TEC protein produces a gain-of-function chimeric product.

Dutton-Regester K, Aoude LG, Nancarrow DJ, et al.
Identification of TFG (TRK-fused gene) as a putative metastatic melanoma tumor suppressor gene.
Genes Chromosomes Cancer. 2012; 51(5):452-61 [PubMed] Related Publications
High density SNP arrays can be used to identify DNA copy number changes in tumors such as homozygous deletions of tumor suppressor genes and focal amplifications of oncogenes. Illumina Human CNV370 Bead chip arrays were used to assess the genome for unbalanced chromosomal events occurring in 39 cell lines derived from stage III metastatic melanomas. A number of genes previously recognized to have an important role in the development and progression of melanoma were identified including homozygous deletions of CDKN2A (13 of 39 samples), CDKN2B (10 of 39), PTEN (3 of 39), PTPRD (3 of 39), TP53 (1 of 39), and amplifications of CCND1 (2 of 39), MITF (2 of 39), MDM2 (1 of 39), and NRAS (1 of 39). In addition, a number of focal homozygous deletions potentially targeting novel melanoma tumor suppressor genes were identified. Because of their likely functional significance for melanoma progression, FAS, CH25H, BMPR1A, ACTA2, and TFG were investigated in a larger cohort of melanomas through sequencing. Nonsynonymous mutations were identified in BMPR1A (1 of 43), ACTA2 (3 of 43), and TFG (5 of 103). A number of potentially important mutation events occurred in TFG including the identification of a mini mutation "hotspot" at amino acid residue 380 (P380S and P380L) and the presence of multiple mutations in two melanomas. Mutations in TFG may have important clinical relevance for current therapeutic strategies to treat metastatic melanoma.

Tiseo M, Gelsomino F, Bartolotti M, et al.
Anaplastic lymphoma kinase as a new target for the treatment of non-small-cell lung cancer.
Expert Rev Anticancer Ther. 2011; 11(11):1677-87 [PubMed] Related Publications
The anaplastic lymphoma kinase (ALK) gene rearrangement identifies a distinct molecular subset in non-small-cell lung cancer (NSCLC) populations susceptible to targeted inhibition. It consists of a small inversion in the short arm of chromosome 2 between exon 20 of the ALK gene and different exons of the echinoderm microtubule-associated protein-like (EML4) gene. This translocation leads to a chimeric protein with constitutive activation of ALK that possesses an oncogenic activity demonstrated both in vitro and in vivo. Other rare translocation partners for ALK other than EML4 may be found in lung cancers, including TRK-fused gene (TFG) and kinesin family member 5B (KIF5B). ALK-positive patients represent 5-6% of all NSCLCs and they seem to have particular clinicopathological and molecular features. Recently, Phase I-II trial results of crizotinib, a potent dual c-MET and ALK inhibitor, demonstrated its dramatic efficacy in ALK-positive patients with advanced NSCLC. This article will present knowledge on the characteristics of ALK-positive patients, discuss the different methods of ALK rearrangement detection and focus on clinical results of crizotinib.

Endoh K, Nishi M, Ishiguro H, et al.
Identification of phosphorylated proteins involved in the oncogenesis of prostate cancer via Pin1-proteomic analysis.
Prostate. 2012; 72(6):626-37 [PubMed] Related Publications
BACKGROUND: The peptidyl-prolyl isomerase Pin1 regulates a subset of phosphorylated proteins by catalyzing the cis-trans isomerization of their specific phosphorylated Ser/Thr-Pro motifs. Although Pin1 has been shown to be involved in cell transformation and the maintenance of the malignant phenotype in prostate cancer, its specific substrates during these processes have not yet been determined.
METHODS: Cancer-specific phosphorylated proteins were isolated from two human prostate cancer cell lines (PC-3, LNCaP) and the Dunning rat prostate cancer cell lines by GST-pull down analysis with recombinant GST-Pin1 protein. These proteins were then identified by the LC-MS/MS analysis using a Q-Tof micro mass spectrometer and processed for further functional analysis.
RESULTS: We newly identified five prostate cancer-specific Pin1 binding proteins (PINBPs) in this screen. Among these, TRK-fused gene (TFG) was found to be preferentially up-regulated in prostate cancer cell lines and tissues. The targeted inhibition of TFG by specific siRNA resulted in the reduced cell proliferation and the induction of premature senescence in PC3 prostate cancer cells. We further found that TFG can facilitate the cell signaling mediated by NF-kappaB and androgen receptor (AR). Tissue micro-dissection based quantitative RT-PCR analysis of prostate cancer tissues following radical prostatectomy further revealed that TFG expression is closely associated with both a higher probability and shorter period of tumor recurrence following surgery.
CONCLUSIONS: Pin1-based proteomics analysis is a useful tool for the identification of prostate cancer-specific phosphorylated proteins. TFG could be a potential diagnostic and/or prognostic marker and therapeutic target in prostate cancer.

Salido M, Pijuan L, Martínez-Avilés L, et al.
Increased ALK gene copy number and amplification are frequent in non-small cell lung cancer.
J Thorac Oncol. 2011; 6(1):21-7 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
INTRODUCTION: Translocation of the anaplastic lymphoma kinase (ALK) gene is involved in the tumorigenesis of a subset of non-small cell lung carcinomas (NSCLCs) and identifies patients sensitive to ALK inhibitors. ALK copy number changes and amplification, which plays an oncogenic role in tumors such as neuroblastoma, are poorly characterized in NSCLC. We aimed to study the prevalence of ALK copy number changes and their correlation to ALK protein expression, epidermal growth factor receptor (EGFR) status, and clinicopathological data in patients with NSCLC.
METHODS: ALK status was evaluated by fluorescence in situ hybridization (FISH). Specimens with ALK translocation were studied for echinoderm microtubule-associated protein-like 4 (EML4), KIF5B, and TFG status. ALK expression was assessed by immunohistochemistry. EGFR gene and protein status were evaluated in adenocarcinomas. Survival analysis was performed.
RESULTS: One hundred seven NSCLC cases were evaluated. There were two cases of EML4-ALK translocation and one with an atypical translocation of ALK. Both cases of EML4-ALK translocation had ALK protein expression, whereas in the rest, ALK was undetected. Eleven cases (10%) exhibited ALK amplification and 68 (63%) copy number gains. There was an association between ALK amplification and EGFR FISH positivity (p < 0.0001) but not with prognosis. In conclusion, EML4-ALK translocation is a rare event in NSCLC.
CONCLUSION: The study reveals a significant frequency of ALK amplification and its association with EGFR FISH positivity in lung adenocarcinomas. Based on these findings, a potential role of ALK amplification in the response to ALK inhibitors alone or combined with EGFR inhibitors in NSCLC merits further studies.

Kim YS, Hwan JD, Bae S, et al.
Identification of differentially expressed genes using an annealing control primer system in stage III serous ovarian carcinoma.
BMC Cancer. 2010; 10:576 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: Most patients with ovarian cancer are diagnosed with advanced stage disease (i.e., stage III-IV), which is associated with a poor prognosis. Differentially expressed genes (DEGs) in stage III serous ovarian carcinoma compared to normal tissue were screened by a new differential display method, the annealing control primer (ACP) system. The potential targets for markers that could be used for diagnosis and prognosis, for stage III serous ovarian cancer, were found by cluster and survival analysis.
METHODS: The ACP-based reverse transcriptase polymerase chain reaction (RT PCR) technique was used to identify DEGs in patients with stage III serous ovarian carcinoma. The DEGs identified by the ACP system were confirmed by quantitative real-time PCR. Cluster analysis was performed on the basis of the expression profile produced by quantitative real-time PCR and survival analysis was carried out by the Kaplan-Meier method and Cox proportional hazards multivariate model; the results of gene expression were compared between chemo-resistant and chemo-sensitive groups.
RESULTS: A total of 114 DEGs were identified by the ACP-based RT PCR technique among patients with stage III serous ovarian carcinoma. The DEGs associated with an apoptosis inhibitory process tended to be up-regulated clones while the DEGs associated with immune response tended to be down-regulated clones. Cluster analysis of the gene expression profile obtained by quantitative real-time PCR revealed two contrasting groups of DEGs. That is, a group of genes including: SSBP1, IFI6 DDT, IFI27, C11orf92, NFKBIA, TNXB, NEAT1 and TFG were up-regulated while another group of genes consisting of: LAMB2, XRCC6, MEF2C, RBM5, FOXP1, NUDCP2, LGALS3, TMEM185A, and C1S were down-regulated in most patients. Survival analysis revealed that the up-regulated genes such as DDAH2, RNase K and TCEAL2 might be associated with a poor prognosis. Furthermore, the prognosis of patients with chemo-resistance was predicted to be very poor when genes such as RNase K, FOXP1, LAMB2 and MRVI1 were up-regulated.
CONCLUSION: The DEGs in patients with stage III serous ovarian cancer were successfully and reliably identified by the ACP-based RT PCR technique. The DEGs identified in this study might help predict the prognosis of patients with stage III serous ovarian cancer as well as suggest targets for the development of new treatment regimens.

Zhang X, Zhang S, Yang X, et al.
Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression.
Mol Cancer. 2010; 9:188 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: The anaplastic lymphoma kinase (ALK) gene is frequently involved in translocations that lead to gene fusions in a variety of human malignancies, including lymphoma and lung cancer. Fusion partners of ALK include NPM, EML4, TPM3, ATIC, TFG, CARS, and CLTC. Characterization of ALK fusion patterns and their resulting clinicopathological profiles could be of great benefit in better understanding the biology of lung cancer.
RESULTS: RACE-coupled PCR sequencing was used to assess ALK fusions in a cohort of 103 non-small cell lung carcinoma (NSCLC) patients. Within this cohort, the EML4-ALK fusion gene was identified in 12 tumors (11.6%). Further analysis revealed that EML4-ALK was present at a frequency of 16.13% (10/62) in patients with adenocarcinomas, 19.23% (10/52) in never-smokers, and 42.80% (9/21) in patients with adenocarcinomas lacking EGFR and KRAS mutations. The EML4-ALK fusion was associated with non-smokers (P = 0.03), younger age of onset (P = 0.03), and adenocarcinomas without EGFR/KRAS mutations (P = 0.04). A trend towards improved survival was observed for patients with the EML4-ALK fusion, although it was not statistically significant (P = 0.20). Concurrent deletion in EGFR exon 19 and fusion of EML4-ALK was identified for the first time in a Chinese female patient with an adenocarcinoma. Analysis of ALK expression revealed that ALK mRNA levels were higher in tumors positive for the EML-ALK fusion than in negative tumors (normalized intensity of 21.99 vs. 0.45, respectively; P = 0.0018). However, expression of EML4 did not differ between the groups.
CONCLUSIONS: The EML4-ALK fusion gene was present at a high frequency in Chinese NSCLC patients, particularly in those with adenocarcinomas lacking EGFR/KRAS mutations. The EML4-ALK fusion appears to be tightly associated with ALK mRNA expression levels. RACE-coupled PCR sequencing is a highly sensitive method that could be used clinically for the identification of EML4-ALK-positive patients.

Starska K, Forma E, Lewy-Trenda I, et al.
The expression of SOCS1 and TLR4-NFkappaB pathway molecules in neoplastic cells as potential biomarker for the aggressive tumor phenotype in laryngeal carcinoma.
Folia Histochem Cytobiol. 2009; 47(3):401-10 [PubMed] Related Publications
Suppressor of cytokine signaling 1 (SOCS1) is the key regulator of cytokine-mediated innate and adaptive immunity. One of the molecular mechanisms of SOCS1 is connected with inhibition of TLR4-NFkappaB pathway. The relationships among these molecules in laryngeal carcinoma are not exactly known. In this preliminary study we focused on their special activity and role in regulation of development and progression of laryngeal carcinoma. To investigate NFkappaB (p65 subunit) nuclear and cytoplasmic expression in 45 tumor samples of advanced laryngeal carcinoma IHC staining was performed. To determine the mRNA expression levels of TLR4, IRAK1, TRAF6 and SOCS1 in isolated neoplasm cells and non-cancerous adjacent mucosa epithelial cells RT-PCR was used. The invasiveness of laryngeal carcinomas was evaluated according to tumor front grading, TFG, which included tumor-related features (cytoplasmic differentiation, nuclear polymorphism, number of mitoses) and adjacent stroma-related characteristics of the peripheral edge of tumor infiltration (mode of infiltration, depth of invasion and plasmalymphocytic infiltration). The relationships between pT, pN status, the histological G grade, certain clinicopathological characteristics as well as postoperative observation time and the mRNA expression of the molecules mentioned earlier were investigated. Significant differences of TLR4-NFkappaB pathway molecules and SOCS1 mRNA expression in laryngeal tumor cells and normal adjacent mucosa cells as well as significant interconnections of TLR4, SOCS1 and NFkappaB(p65) in isolated tumor cells were obtained. This preliminary study demonstrated that the expression of SOCS1 and TLR4-NFkappaB pathway molecules had a strong association with the aggressiveness of laryngeal carcinoma. Positive relationships of TRAF6 in tumor margin cells with the histological grade and the mode of tumor invasion as well as the TFG total score were highlighted. Significant positive correlations were found between the TLR4 in tumor central cells and the TFG total score. Negative relationships of SOCS1 in tumor central cells with the histological grade were also noted. Significant positive correlations were found between the cytoplasmic NFkappaB(p65) and the mode of invasion as well as TFG total score. Our findings confirmed the importance of SOCS1 and TLR4-NFkappaB pathway molecules as potential biomarkers for assessment of the aggressive tumor phenotype in laryngeal carcinoma.

Hegyi H, Buday L, Tompa P
Intrinsic structural disorder confers cellular viability on oncogenic fusion proteins.
PLoS Comput Biol. 2009; 5(10):e1000552 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Chromosomal translocations, which often generate chimeric proteins by fusing segments of two distinct genes, represent the single major genetic aberration leading to cancer. We suggest that the unifying theme of these events is a high level of intrinsic structural disorder, enabling fusion proteins to evade cellular surveillance mechanisms that eliminate misfolded proteins. Predictions in 406 translocation-related human proteins show that they are significantly enriched in disorder (43.3% vs. 20.7% in all human proteins), they have fewer Pfam domains, and their translocation breakpoints tend to avoid domain splitting. The vicinity of the breakpoint is significantly more disordered than the rest of these already highly disordered fusion proteins. In the unlikely event of domain splitting in fusion it usually spares much of the domain or splits at locations where the newly exposed hydrophobic surface area approximates that of an intact domain. The mechanisms of action of fusion proteins suggest that in most cases their structural disorder is also essential to the acquired oncogenic function, enabling the long-range structural communication of remote binding and/or catalytic elements. In this respect, there are three major mechanisms that contribute to generating an oncogenic signal: (i) a phosphorylation site and a tyrosine-kinase domain are fused, and structural disorder of the intervening region enables intramolecular phosphorylation (e.g., BCR-ABL); (ii) a dimerisation domain fuses with a tyrosine kinase domain and disorder enables the two subunits within the homodimer to engage in permanent intermolecular phosphorylations (e.g., TFG-ALK); (iii) the fusion of a DNA-binding element to a transactivator domain results in an aberrant transcription factor that causes severe misregulation of transcription (e.g. EWS-ATF). Our findings also suggest novel strategies of intervention against the ensuing neoplastic transformations.

Greco A, Miranda C, Pierotti MA
Rearrangements of NTRK1 gene in papillary thyroid carcinoma.
Mol Cell Endocrinol. 2010; 321(1):44-9 [PubMed] Related Publications
TRK oncogenes are observed in a consistent fraction of papillary thyroid carcinoma (PTC); they arise from the fusion of the 3' terminal sequences of the NTRK1/NGF receptor gene with 5' terminal sequences of various activating genes, such as TPM3, TPR and TFG. TRK oncoproteins display constitutive tyrosine-kinase activity, leading to in vitro and in vivo transformation. In this review studies performed during the last 20 years will be summarized. The following topics will be illustrated: (a) frequency of TRK oncogenes and correlation with radiation and tumor histopathological features; (b) molecular mechanisms underlying NTRK1 oncogenic rearrangements; (c) molecular and biochemical characterization of TRK oncoproteins, and their mechanism of action; (d) role of activating sequences in the activation of TRK oncoproteins.

Lee YS, Choi HB, Lee IK, et al.
Association between interleukin-4R and TGF-β1 gene polymorphisms and the risk of colorectal cancer in a Korean population.
Colorectal Dis. 2010; 12(12):1208-12 [PubMed] Related Publications
AIM: Colorectal cancer is associated with inflammatory bowel disease. The mechanisms of how different genetic make-ups of cytokines might influence the individual susceptibility to develop particular types of tumours are still unknown. The authors analysed the association between genetic polymorphisms in cytokine/cytokine receptor genes and the risk of colorectal cancer in a Korean population.
METHOD: The authors assessed polymorphisms of the interleukin: IL-1, IL-1R, IL-2, IL-4, IL-4R, IL-10, transforming growth factor (TGF)-β1, IFN-γ genes in Korean patients with colorectal cancer (n = 170) and in a normal healthy control group (n = 130) to investigate the association between theses cytokine gene polymorphisms and the risk of colorectal cancer.
RESULTS: The IL-4R 1902*T allele was found to be associated with an increased risk of colon cancer (P < 0.01, OR = 2.0) and rectal cancer (P < 0.05, OR = 1.8). The IL-4R 1902*C allele was associated with a decreased risk of both colon cancer (P < 0.01, OR = 0.51) and rectal cancer (P < 0.05, OR = 0.5). The TFG-β1 10*T allele was found to be associated with an increased risk of colon cancer (P < 0.00, OR = 2.3) and the TFG-β1 10*C allele with a decreased risk of colon cancer (P < 0.00, OR = 0.43).
CONCLUSION: These results suggest that the genetic polymorphisms of IL-4R and TGF-β1 are associated with the risk of colorectal cancer in a Korean population.

Chase A, Ernst T, Fiebig A, et al.
TFG, a target of chromosome translocations in lymphoma and soft tissue tumors, fuses to GPR128 in healthy individuals.
Haematologica. 2010; 95(1):20-6 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: The formation of fusion genes plays roles in both oncogenesis and evolution by facilitating the acquisition of novel functions. Here we describe the first example of a human polymorphic in-frame fusion of two unrelated genes associated with a copy number variant.
DESIGN AND METHODS: Array comparative genomic hybridization was used to identify cryptic oncogenic fusion genes. Fusion gene structure and origin was examined using molecular biological and computational methods. Phenotype associations were examined using PopGen cohorts.
RESULTS: Targeted array comparative genomic hybridization to identify cryptic oncogenic fusion genes in patients with atypical myeloproliferative neoplasms identified a 111 kb amplification with breakpoints within the TRK-fused gene (TFG, a target of translocations in lymphoma and thyroid tumors) and G-protein-coupled receptor 128 (GPR128) resulting in an expressed in-frame TFG-GPR128 fusion transcript. The fusion gene was also identified in healthy individuals at a frequency of 0.02 (3/120). Normally both genes are in identical orientations with TFG immediately downstream of GPR128. In individuals with a copy number variant amplification, one or two copies of the TFG-GPR128 fusion are found between the two parental genes. The breakpoints share a region of microhomology, and haplotype and microsatellite analysis indicate a single ancestral origin. Analysis of PopGen cohorts showed no obvious phenotype association. An in silico search of EST databases found no other copy number variant amplification-associated fusion transcripts, suggesting that this is an uncommon event. Conclusions The finding of a polymorphic gene fusion in healthy individuals adds another layer to the complexity of human genome variation and emphasizes the importance of careful discrimination of oncogenic changes found in tumor samples from non-pathogenic normal variation.

Li H, Sekine M, Seng S, et al.
BRCA1 interacts with Smad3 and regulates Smad3-mediated TGF-beta signaling during oxidative stress responses.
PLoS One. 2009; 4(9):e7091 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: BRCA1 is a key regulatory protein participating in cell cycle checkpoint and DNA damage repair networks. BRCA1 plays important roles in protecting numerous cellular processes in response to cell damaging signals. Transforming growth factor-beta (TGF-beta) is a potent regulator of growth, apoptosis and invasiveness of tumor cells. TFG-beta activates Smad signaling via its two cell surface receptors, the TbetaRII and ALK5/TbetaRI, leading to Smad-mediated transcriptional regulation.
METHODOLOGY/PRINCIPAL FINDINGS: Here, we report an important role of BRCA1 in modulating TGF-beta signaling during oxidative stress responses. Wild-type (WT) BRCA1, but not mutated BRCA1 failed to activate TGF-beta mediated transactivation of the TGF-beta responsive reporter, p3TP-Lux. Further, WT-BRCA1, but not mutated BRCA1 increased the expression of Smad3 protein in a dose-dependent manner, while silencing of WT-BRCA1 by siRNA decreased Smad3 and Smad4 interaction induced by TGF-beta in MCF-7 breast cancer cells. BRCA1 interacted with Smad3 upon TGF-beta1 stimulation in MCF-7 cells and this interaction was mediated via the domain of 298-436aa of BRCA1 and Smad3 domain of 207-426aa. In addition, H(2)O(2) increased the colocalization and the interaction of Smad3 with WT-BRCA1. Interestingly, TGF-beta1 induced Smad3 and Smad4 interaction was increased in the presence of H(2)O(2) in cells expressing WT-BRCA1, while the TGF-beta1 induced interaction between Smad3 and Smad4 was decreased upon H(2)O(2) treatment in a dose-dependent manner in HCC1937 breast cancer cells, deficient for endogenous BRCA1. This interaction between Smad3 and Smad4 was increased in reconstituted HCC1937 cells expressing WT-BRCA1 (HCC1937/BRCA1). Further, loss of BRCA1 resulted in H(2)O(2) induced nuclear export of phosphor-Smad3 protein to the cytoplasm, resulting decreased of Smad3 and Smad4 interaction induced by TGF-beta and in significant decrease in Smad3 and Smad4 transcriptional activities.
CONCLUSIONS/SIGNIFICANCE: These results strongly suggest that loss or reduction of BRCA1 alters TGF-beta growth inhibiting activity via Smad3 during oxidative stress responses.

Damm-Welk C, Klapper W, Oschlies I, et al.
Distribution of NPM1-ALK and X-ALK fusion transcripts in paediatric anaplastic large cell lymphoma: a molecular-histological correlation.
Br J Haematol. 2009; 146(3):306-9 [PubMed] Related Publications
Anaplastic large cell lymphomas (ALCL) in children express anaplastic lymphoma kinase (ALK) fusion genes, most commonly NPM1-ALK. The distribution of X-ALK among 66 childhood ALCLs was analysed. One ALCL was ALK-negative. Reverse transcription polymerase chain reaction detected NPM1-ALK in 58 tumours, all showing nuclear and cytoplasmic ALK staining. The remaining seven ALCL stained for ALK in the cytoplasm only: two expressed TPM3-ALK, one ATIC-ALK, one MYH9-ALK; three no TPM3-, TFG-, ATIC-, CLTC- or MYH9-ALK. Almost 90% of paediatric ALK-positive ALCLs express NPM1-ALK. There was complete concordance between ALK staining pattern and the presence of a typical/variant ALK fusion partner.

Shinmura K, Kageyama S, Tao H, et al.
EML4-ALK fusion transcripts, but no NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts, in non-small cell lung carcinomas.
Lung Cancer. 2008; 61(2):163-9 [PubMed] Related Publications
EML4-ALK gene fusions have recently been discovered in a subset of human lung carcinomas, and fusions of the ALK tyrosine kinase gene with the NPM, TPM3, CLTC, ATIC, and TFG genes have been found in hematological malignancies. To elucidate the role of fusions between ALK and other genes in pulmonary carcinogenesis, we examined 77 non-small cell lung carcinomas (NSCLCs) for EML4-, NPM-, TPM3-, CLTC-, ATIC-, and TFG-ALK fusion transcripts by RT-PCR and subsequent sequencing analysis. Although no expression of NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts were detected in any of the cases, expression of EML4-ALK fusion transcripts was detected in two (2.6%) of the 77 NSCLCs. In one of the two NSCLCs there was fusion between exon 13 of EML4 and exon 20 of ALK, i.e., variant 1, and in the other there was fusion between exon 20 of EML4 and exon 20 of ALK, i.e., variant 2. Both patients had a history of smoking, and histologically the carcinomas were adenocarcinoma. No somatic mutations were detected in the mutation cluster regions of the EGFR, K-RAS, and PIK3CA genes in these two carcinomas, however, a Pro177Ser mutation of the p53 gene was detected in the carcinoma that contained the variant 1 EML4-ALK fusion transcripts. In situ PCR of a paraffin block section showed that the carcinoma with expression of the variant 1 actually contained an EML4-ALK fusion gene. These results suggested that the EML4-ALK fusion gene product is involved in the carcinogenesis of a subset of NSCLCs.

Starska K, Łukomski M, Stasikowska O, Lewy-Trenda I
Prognostic significance of matrix metalloproteinases type I expression and tumor front parameters in the presence of lymph node micrometastases in carcinoma of the larynx.
Adv Med Sci. 2007; 52:169-73 [PubMed] Related Publications
PURPOSE: Lymph nodes estimated as pNO in conventional morphological studies could have focuses of carcinoma cells with a diameter of < or =2 mm referred to as micrometastases (pN+). Matrix metalloproteinases (MMPs) are proteolytic family of endopeptidases which are capable to degrading components of the extracellular matrix and play an important role in cancer invasion and metastases. The aim of this study was to investigate MT1-MMP expression in carcinoma of the larynx and analyze morphological parameters to relate the expression to CKs in pN0 lymph nodes.
MATERIAL AND METHODS: To presented the direct correlation between 6 morphological features of tumor front and the probability of micrometastases and prediction of prognosis 22 patients operated for squamous cell carcinoma of the larynx were analyzed. The total score of TFG, chosen clinicomorphological features and grade of matrix metalloproteinase membrane type 1 staining in tumor front were analyzed to predict the presence of micrometastases and prognosis. Immunohistochemical methods with a panel of CKs antigens in lymph nodes and MT1-MMP expression in tumor tissue were per-lymph nodes. There was no significant relationship for immunoexpression of MT1-MMP and positive poliCKs stain.
CONCLUSIONS: The results of study suggest that extended traditional pathologic evaluation by features from the TFG classification could aid in diagnosis of micrometastases. The positive expression of poliCKs in the pN0 lymph nodes appears to play an important role in determining prognosis in patients with carcinoma of the larynx.

Okada H, Lieberman FS, Walter KA, et al.
Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of patients with malignant gliomas.
J Transl Med. 2007; 5:67 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: The prognosis for malignant gliomas remains dismal. We addressed the safety, feasibility and preliminary clinical activity of the vaccinations using autologous glioma cells and interleukin (IL)-4 gene transfected fibroblasts.
METHODS: In University of Pittsburgh Cancer Institute (UPCI) protocol 95-033, adult participants with recurrent glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) received gross total resection (GTR) of the recurrent tumors, followed by two vaccinations with autologous fibroblasts retrovirally transfected with TFG-IL4-Neo-TK vector admixed with irradiated autologous glioma cells. In UPCI 99-111, adult participants with newly diagnosed GBM or AA, following GTR and radiation therapy, received two intradermal vaccinations with the TFG-IL4-Neo-TK-transfected fibroblasts admixed with type-1 dendritic cells (DC) loaded with autologous tumor lysate. The participants were evaluated for occurrence of adverse events, immune response, and clinical response by radiological imaging.
RESULTS AND DISCUSSION: In UPCI 95-033, only 2 of 6 participants received the vaccinations. Four other participants were withdrawn from the trial because of tumor progression prior to production of the cellular vaccine. However, both participants who received two vaccinations demonstrated encouraging immunological and clinical responses. Biopsies from the local vaccine sites from one participant displayed IL-4 dose-dependent infiltration of CD4+ as well as CD8+ T cells. Interferon (IFN)-gamma Enzyme-Linked Immuno-SPOT (ELISPOT) assay in another human leukocyte antigen (HLA)-A2+ participant demonstrated systemic T-cell responses against an HLA-A2-restricted glioma-associated antigen (GAA) epitope EphA2883-891. Moreover, both participants demonstrated clinical and radiological improvement with no evidence of allergic encephalitis, although both participants eventually succumbed with the tumor recurrence. In 99-111, 5 of 6 enrolled participants received scheduled vaccinations with no incidence of major adverse events. Monocyte-derived DCs produced high levels of IL-12 p70. Treatment was well tolerated; however, we were unable to observe detectable IFN-gamma post-vaccine responses or prolonged progression-free survival in these participants.
CONCLUSION: Feasibility challenges inherent in the generation of a patient-specific gene transfection-based vaccine strongly suggests the need for more practical formulations that would allow for the timely administration of vaccines. Nevertheless, successful generation of type-1 DCs and preliminary safety in the current study provide a strong rationale for further efforts to develop novel glioma vaccines.

Li C, Takino H, Eimoto T, et al.
Prognostic significance of NPM-ALK fusion transcript overexpression in ALK-positive anaplastic large-cell lymphoma.
Mod Pathol. 2007; 20(6):648-55 [PubMed] Related Publications
In anaplastic large-cell lymphomas positive for anaplastic lymphoma kinase (ALK) protein, the ALK gene is most commonly fused to the NPM gene, and less commonly to TPM3, TFG, ATIC, and other rare genes. Although this lymphoma is generally associated with a favorable clinical outcome, 25% of the patients die of the disease within 5 years. In this study, we developed three assays, all of which can be used with archival formalin-fixed, paraffin-embedded tissues: (1) a sensitive reverse transcription-polymerase chain reaction (RT-PCR) assay for various X-ALK fusion genes, (2) a 5' rapid amplification of cDNA ends (RACE) assay to identify unknown fusion partners, and (3) a real-time RT-PCR assay to quantify the amount of the NPM-ALK fusion transcript. In 26 cases of ALK(+) anaplastic large-cell lymphoma, the RT-PCR assay showed that the ALK was fused to NPM in 21 cases, to TPM3 in three, and to TFG in one. The 5' RACE assay detected ATIC-ALK fusion in the remaining case. The real-time quantitative RT-PCR assay showed that the NPM-ALK transcript was over expressed in four of 20 quantifiable cases. Patients with NPM-ALK overexpression showed a significantly unfavorable overall survival compared with those with a low expression of this transcript. The RT-PCR and 5' RACE assays developed here may be useful for identification of known and unknown gene partners fused to the ALK gene. Overexpression of the NPM-ALK fusion transcript may be associated with a poor prognosis of the patients with ALK(+) anaplastic large-cell lymphomas.

Herlevsen M, Oxford G, Ptak C, et al.
A novel model to identify interaction partners of the PTEN tumor suppressor gene in human bladder cancer.
Biochem Biophys Res Commun. 2007; 352(2):549-55 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Phosphatase and tensin homolog (PTEN), deleted on chromosome 10, is a potent tumor suppressor. PTEN expression is reduced in advanced bladder cancer and reduction correlates with disease stage. To gain insights into the function of PTEN in human bladder cancer by identifying its binding partners, we developed a novel IPTG inducible PTEN expression system and evaluated this system in the PTEN null UMUC-3 human bladder cancer xenograft model. In this model, induction of PTEN in vivo resulted in reduced tumor growth. We used mass spectrometry to identify PTEN interaction partners in these cells, which identified known interaction partners major vault protein (MVP) and paxillin as well as a novel interaction partner, TRK fused gene (TFG). In conclusion, using a biologically relevant model system to dissect PTEN tumor suppressor function in human bladder cancer, we identified three molecules important for many cellular functions in complex with PTEN.

Tateishi U, Hasegawa T, Nojima T, et al.
MRI features of extraskeletal myxoid chondrosarcoma.
Skeletal Radiol. 2006; 35(1):27-33 [PubMed] Related Publications
OBJECTIVE: To describe the MRI features of extraskeletal myxoid chondrosarcoma in comparison with clinicopathologic findings.
DESIGN AND PATIENTS: The study comprised 12 male subjects and seven female subjects with a mean age of 53 years (range 16-76 years). MRI findings, evaluated by two radiologists with agreement by consensus, were compared for histopathologic features.
RESULTS: The tumor size ranged from 2.0 cm to 20.0 cm (mean 8.9 cm). Fusion gene transcripts could be detected in 13 (68%) of the 19 cases: EWS-CHN in nine cases, TAF2N-CHN in three, and TFG-TCH in one. There were six fusion-negative cases. Signal characteristics on T1-weighted and T2-weighted MR images were non-specific with regard to each cytogenetic variant. Peripheral enhancement was seen more frequently in tumors with the EWS-CHN variant than in those with other cytogenetic variants. The characteristic pattern of enhancement corresponded to the presence of fibrous septa and peripheral areas of high cellularity within lobules, by correlation with pathologic findings. All cases with TAF2N-CHN or TFG-TCH variants showed invasion of extracompartmental structure, bone, or vessels.
CONCLUSION: Extraskeletal myxoid chondrosarcoma is an uncommon soft-tissue malignancy that may be recognized by MRI features of multi-lobular soft-tissue mass often invading extracompartmental, bony, and vascular structures.

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