ETV1

Gene Summary

Gene:ETV1; ets variant 1
Aliases: ER81
Location:7p21.3
Summary:This gene encodes a member of the ETS (E twenty-six) family of transcription factors. The ETS proteins regulate many target genes that modulate biological processes like cell growth, angiogenesis, migration, proliferation and differentiation. All ETS proteins contain an ETS DNA-binding domain that binds to DNA sequences containing the consensus 5'-CGGA[AT]-3'. The protein encoded by this gene contains a conserved short acidic transactivation domain (TAD) in the N-terminal region, in addition to the ETS DNA-binding domain in the C-terminal region. This gene is involved in chromosomal translocations, which result in multiple fusion proteins including EWS-ETV1 in Erwing sarcoma and at least 10 ETV1 partners (see PMID: 19657377, Table 1) in prostate cancer. In addition to chromosomal rearrangement, this gene is overexpressed in prostate cancer, melanoma and gastrointestinal stromal tumor. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:ETS translocation variant 1
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
Show (10)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

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

  • FISH
  • Gene Fusion
  • TMPRSS2
  • Tumor Markers
  • Cancer Gene Expression Regulation
  • Gene Expression Profiling
  • Neoplasm Invasiveness
  • Melanoma
  • Adolescents
  • Childhood Cancer
  • Trans-Activators
  • Proto-Oncogene Proteins
  • Tissue Array Analysis
  • Transcription Factors
  • Adenocarcinoma
  • Androgen Receptors
  • Messenger RNA
  • Oligonucleotide Array Sequence Analysis
  • RNA-Binding Protein EWS
  • Neoplastic Cell Transformation
  • Base Sequence
  • Cohort Studies
  • Molecular Sequence Data
  • Gene Rearrangement
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins c-ets
  • Immunohistochemistry
  • Paraffin Embedding
  • ETV1
  • Chromosome 7
  • Neoplasm Proteins
  • Adenovirus E1A Proteins
  • Translocation
  • Oncogene Fusion Proteins
  • EWSR1
  • Recombinant Fusion Proteins
  • Ewing's Sarcoma
  • Gastrointestinal Stromal Tumors
  • Prostate Cancer
  • Polymerase Chain Reaction
  • Staging
  • RTPCR
  • Promoter Regions
  • Bone Cancer
  • Chromosome Aberrations
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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

Entity Topic PubMed Papers
Prostate CancerETV1 translocations in Prostate Cancer
Gene fusions involving the erythroblast transformation-specific (ETS) transcription factors ERG, ETV1, ETV4, ETV5, and FLI1 are a common feature of prostate carcinomas. Most frequently, the androgen-activated gene TMPRSS2 is fused to the ERG gene, but less frequently involving ETV1, ETV4 ,ETV5 and over 12 fusion partners identified so far.
View Publications73
Ewing's Sarcoma t(7;22)(p22;q12) EWS-ETV1 Translocation in Ewing's Sarcoma View Publications24
Gastrointestinal Stromal TumorsETV1 overexpression in Gastrointestinal Stromal Tumours View Publications12
MelanomaETV1 overexpression in Melanoma View Publications2

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

Latest Publications: ETV1 (cancer-related)

Labussière M, Di Stefano AL, Gleize V, et al.
TERT promoter mutations in gliomas, genetic associations and clinico-pathological correlations.
Br J Cancer. 2014; 111(10):2024-32 [PubMed] Article available free on PMC after 11/11/2015 Related Publications
BACKGROUND: The role of telomerase reverse transcriptase (TERT) in gliomagenesis has been recently further strengthened by the frequent occurrence of TERT promoter mutations (TERTp-mut) in gliomas and evidence that the TERT SNP genetic rs2736100 influences glioma risk. TERTp-mut creates a binding site for Ets/TCF transcription factors, whereas the common rs2853669 polymorphism disrupts another Ets/TCF site on TERT promoter.
METHODS: We sequenced for TERTp-mut in 807 glioma DNAs and in 235 blood DNAs and analysed TERT expression by RT-PCR in 151 samples. TERTp-mut status and TERTp polymorphism rs2853669 were correlated with histology, genomic profile, TERT mRNA expression, clinical outcome and rs2736100 genotype.
RESULTS: TERTp-mut identified in 60.8% of gliomas (491 out of 807) was globally associated with poorer outcome (Hazard ratio (HR)=1.50). We defined, based on TERTp-mut and IDH mutation status, four prognostic groups: (1) TERTp-mut and IDH-mut associated with 1p19q codeletion, overall survival (OS)>17 years; (2) TERTp-wt and IDH-mut, associated with TP53 mutation, OS=97.5 months; (3) TERTp-wt and IDH-wt, with no specific association, OS=31.6 months; (4) TERTp-mut and IDH-wt, associated with EGFR amplification, OS=15.4 months. TERTp-mut was associated with higher TERT mRNA expression, whereas the rs2853669 variant was associated with lower TERT mRNA expression. The mutation of CIC (a repressor of ETV1-5 belonging to the Ets/TCF family) was also associated with TERT mRNA upregulation.
CONCLUSIONS: In addition to IDH mutation status, defining the TERTp-mut status of glial tumours should afford enhanced prognostic stratification of patients with glioma. We also show that TERTp-mut, rs2853669 variant and CIC mutation influence Tert expression. This effect could be mediated by Ets/TCF transcription factors.

Schoppmann SF, Ricken G, Ilhan-Mutlu A, et al.
Downregulation of CIC does not associate with overexpression of ETV1 or MAP kinase pathway activation in gastrointestinal stromal tumors.
Cancer Invest. 2014; 32(7):363-7 [PubMed] Related Publications
ETV1 is a key factor in gastrointestinal stromal tumors (GIST), and is promoted by CIC downregulation in melanoma. We investigated CIC, ETV1, and the MAPK pathway in GIST. Downregulation of CIC protein levels as assessed by immunostaining was seen in 17/144 GIST, but was not associated with ETV1 or pMEK1/2 expression, KIT and PDGFRA mutations, copy number variations (CNV) of 19q13, and clinical factors. However, the data indicate that the incidence of CIC downregulation may differ for GISTs in different locations in the gastrointestinal tract, and that CNV of 19q13 is associated with shorter disease-free survival.

Dong J, Xiao L, Sheng L, et al.
TMPRSS2:ETS fusions and clinicopathologic characteristics of prostate cancer patients from Eastern China.
Asian Pac J Cancer Prev. 2014; 15(7):3099-103 [PubMed] Related Publications
TMPRSS2:ERG gene fusions in prostate cancer have a dominant prevalence of approximately 50.0%, but infomration is limited on differences among ethnic and geographical groups. Some studies focusing on Japanese and Korean patients reported a lower incidence. Investigations concerning Chinese revealed controversial results. We evaluated TMPRSS2:ERG, TMPRSS2:ETV1 and TMPRSS2:ETV4 fusions in more than 100 Eastern Chinese prostate cancer patients. Paraffin blocks of needle biopsy and radical prostatectomy were collected from 91 and 18 patients respectively. All patients' clinicopathologic factors were gathered. TMPRSS2:ERG, TMPRSS2:ETV1 and TMPRSS2:ETV4 fusions were tested by multi-probe fluorescence in situ hybridization (FISH) assay. TMPRSS2:ERG fusions was present in 14.3% biopsy specimens and 11.1% radical prostatectomy patients. Neither TMPRSS2:ETV1 nor TMPRSS2:ETV4 fusion was found in any case. Altogether, 13 (86.7%) TMPRSS2:ERG fusion positive cases possessed deletion pattern and 7 (46.6%) and insertion pattern. Some 5 cases had both deletion and insertion patterns. While 38.5% (5/13) patients with deletion pattern had distant metastasis, except for one metastatic case harboring both deletion and insertion, there were no patients with insertion pattern accompanied with metastasis. There were no differences between fusion positive and negative cases in the distribution of age, PSA, Gleason score and TNM stage. Eastern Chinese prostate cancer patients have a significantly low incidence of TMPRSS2:ERG fusion. They also lack TMPRSS2:ETV1 and TMPRSS2:ETV4 fusion. There are more deletion pattern than insertion pattern in TMPRSS2:ERG positive cases. Fusion positive and negative patients have no clinicopathologic factor differences.

Sharma NL, Massie CE, Butter F, et al.
The ETS family member GABPα modulates androgen receptor signalling and mediates an aggressive phenotype in prostate cancer.
Nucleic Acids Res. 2014; 42(10):6256-69 [PubMed] Article available free on PMC after 11/11/2015 Related Publications
In prostate cancer (PC), the androgen receptor (AR) is a key transcription factor at all disease stages, including the advanced stage of castrate-resistant prostate cancer (CRPC). In the present study, we show that GABPα, an ETS factor that is up-regulated in PC, is an AR-interacting transcription factor. Expression of GABPα enables PC cell lines to acquire some of the molecular and cellular characteristics of CRPC tissues as well as more aggressive growth phenotypes. GABPα has a transcriptional role that dissects the overlapping cistromes of the two most common ETS gene fusions in PC: overlapping significantly with ETV1 but not with ERG target genes. GABPα bound predominantly to gene promoters, regulated the expression of one-third of AR target genes and modulated sensitivity to AR antagonists in hormone responsive and castrate resistant PC models. This study supports a critical role for GABPα in CRPC and reveals potential targets for therapeutic intervention.

Pop MS, Stransky N, Garvie CW, et al.
A small molecule that binds and inhibits the ETV1 transcription factor oncoprotein.
Mol Cancer Ther. 2014; 13(6):1492-502 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Members of the ETS transcription factor family have been implicated in several cancers, where they are often dysregulated by genomic derangement. ETS variant 1 (ETV1) is an ETS factor gene that undergoes chromosomal translocation in prostate cancers and Ewing sarcomas, amplification in melanomas, and lineage dysregulation in gastrointestinal stromal tumors. Pharmacologic perturbation of ETV1 would be appealing in these cancers; however, oncogenic transcription factors are often deemed "undruggable" by conventional methods. Here, we used small-molecule microarray screens to identify and characterize drug-like compounds that modulate the biologic function of ETV1. We identified the 1,3,5-triazine small molecule BRD32048 as a top candidate ETV1 perturbagen. BRD32048 binds ETV1 directly, modulating both ETV1-mediated transcriptional activity and invasion of ETV1-driven cancer cells. Moreover, BRD32048 inhibits p300-dependent acetylation of ETV1, thereby promoting its degradation. These results point to a new avenue for pharmacologic ETV1 inhibition and may inform a general means to discover small molecule perturbagens of transcription factor oncoproteins.

Specht K, Sung YS, Zhang L, et al.
Distinct transcriptional signature and immunoprofile of CIC-DUX4 fusion-positive round cell tumors compared to EWSR1-rearranged Ewing sarcomas: further evidence toward distinct pathologic entities.
Genes Chromosomes Cancer. 2014; 53(7):622-33 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Round cell sarcomas harboring CIC-DUX4 fusions have recently been described as highly aggressive soft tissue tumors of children and young adults. Due to partial morphologic and immunohistochemical overlap with Ewing sarcoma (ES), CIC-DUX4-positive tumors have generally been classified as ES-like and managed similarly; however, a systematic comparison at the molecular and immunohistochemical levels between these two groups has not yet been conducted. Based on an initial observation that CIC-DUX4-positive tumors show nuclear immunoreactivity for WT1 and ETS transcription factors, FLI1 and ERG, we performed a detailed immunohistochemical and molecular analysis including these markers, to further investigate the relationship between CIC-DUX4 tumors and ES. The study group included 21 CIC-DUX4-positive sarcomas and 20 EWSR1-rearranged ES. Immunohistochemically, CIC-DUX4 sarcomas showed membranous CD99 positivity in 18 (86%) cases, but only 5 (24%) with a diffuse pattern, while WT1 and FLI1 were strongly positive in all cases. ERG was positive in 18% of cases. All ES expressed CD99 and FLI1, while ERG positivity was only seen in EWSR1-ERG fusion positive ES. WT1 was negative in all ES. Expression profiling validated by q-PCR revealed a distinct gene signature associated with CIC-DUX4 fusion, with upregulation of ETS transcription factors (ETV4, ETV1, and ETV5) and WT1, among top overexpressed genes compared to ES, other sarcomas and normal tissue. In conclusion, the distinct gene signature and immunoprofile of CIC-DUX4 sarcomas suggest a distinct pathogenesis from ES. The consistent WT1 expression may provide a useful clue in the diagnosis in the context of round cell sarcomas negative for EWSR1 rearrangement. © 2014 Wiley Periodicals, Inc.

Gasi Tandefelt D, Boormans J, Hermans K, Trapman J
ETS fusion genes in prostate cancer.
Endocr Relat Cancer. 2014; 21(3):R143-52 [PubMed] Related Publications
Prostate cancer is very common in elderly men in developed countries. Unravelling the molecular and biological processes that contribute to tumor development and progressive growth, including its heterogeneity, is a challenging task. The fusion of the genes ERG and TMPRSS2 is the most frequent genomic alteration in prostate cancer. ERG is an oncogene that encodes a member of the family of ETS transcription factors. At lower frequency, other members of this gene family are also rearranged and overexpressed in prostate cancer. TMPRSS2 is an androgen-regulated gene that is preferentially expressed in the prostate. Most of the less frequent ETS fusion partners are also androgen-regulated and prostate-specific. During the last few years, novel concepts of the process of gene fusion have emerged, and initial experimental results explaining the function of the ETS genes ERG and ETV1 in prostate cancer have been published. In this review, we focus on the most relevant ETS gene fusions and summarize the current knowledge of the role of ETS transcription factors in prostate cancer. Finally, we discuss the clinical relevance of TMRPSS2-ERG and other ETS gene fusions in prostate cancer.

Olumi AF
Commentary on "ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients." Baena E, Shao Z, Linn DE, Glass K, Hamblen MJ, Fujiwara Y, Kim J, Nguyen M, Zhang X, Godinho FJ, Bronson RT, Mucci LA, Loda M, Yuan GC, Orkin SH, Li Z, Division of Hematology and Oncology, Boston Children's Hospital, Boston, MA, USA.: Genes Dev 2013;27(6):683-98.
Urol Oncol. 2014; 32(2):213 [PubMed] Related Publications
Distinguishing aggressive from indolent disease and developing effective therapy for advanced disease are the major challenges in prostate cancer research. Chromosomal rearrangements involving ETS transcription factors, such as ERG and ETV1, occur frequently in prostate cancer. How they contribute to tumorigenesis and whether they play similar or distinct in vivo roles remain elusive. Here we show that in mice with ERG or ETV1 targeted to the endogenous Tmprss2 locus, either factor cooperated with loss of a single copy of Pten, leading to localized cancer, but only ETV1 appeared to support development of invasive adenocarcinoma under the background of full Pten loss. Mechanistic studies demonstrated that ERG and ETV1 control a common transcriptional network but largely in an opposing fashion. In particular, while ERG negatively regulates the androgen receptor (AR) transcriptional program, ETV1 cooperates with AR signaling by favoring activation of the AR transcriptional program. Furthermore, we found that ETV1 expression, but not that of ERG, promotes autonomous testosterone production. Last, we confirmed the association of an ETV1 expression signature with aggressive disease and poorer outcome in patient data. The distinct biology of ETV1-associated prostate cancer suggests that this disease class may require new therapies directed to underlying programs controlled by ETV1.

Li Z, Zhang L, Ma Z, et al.
ETV1 induces epithelial to mesenchymal transition in human gastric cancer cells through the upregulation of Snail expression.
Oncol Rep. 2013; 30(6):2859-63 [PubMed] Related Publications
The ETS family of transcription factors is involved in several physiological and pathological processes including tumor progression. The ETS transcription factors are divided into subfamilies based on the sequence and location of the ETS domain. ETV1 (Ets variant gene 1; also known as ER81), is a member of the PEA3 subfamily, which has been found to promote metastatic progression in several types of human cancer. Previous findings demonstrated that ETV1 expression is upregulated in gastric adenocarcinomas; however, the underlying mechanisms of ETV1-induced metastatic progression in gastric cancer remain elusive. In the present study, we found that the overexpression of ETV1 in normal gastric epithelial cells resulted in epithelial to mesenchymal transition (EMT) and increased invasiveness. Conversely, knockdown of ETV1 resulted in decreased aggressiveness of the invasive gastric cancer cells. Mechanistically, ETV1 transcriptionally upregulates Snail expression. Of note, ETV1 expression is significantly correlated with Snail expression in human gastric tumor samples. In summary, we present data that ETV1 promotes Snail expression to induce EMT-like metastatic progression in gastric cancer.

Mathew G, Mitchell A, Down JM, et al.
Nuclear targeting of dystroglycan promotes the expression of androgen regulated transcription factors in prostate cancer.
Sci Rep. 2013; 3:2792 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Dystroglycan is frequently lost in adenocarcinoma, but the mechanisms and consequences are poorly understood. We report an analysis of β-dystroglycan in prostate cancer in human tissue samples and in LNCaP cells in vitro. There is progressive loss of β-dystroglycan immunoreactivity from basal and lateral surfaces of prostate epithelia which correlates significantly with increasing Gleason grade. In about half of matched bone metastases there is significant dystroglycan re-expression. In tumour tissue and in LNCaP cells there is also a tyrosine phosphorylation-dependent translocation of β-dystroglycan to the nucleus. Analysis of gene expression data by microarray, reveals that nuclear targeting of β-dystroglycan in LNCaP cells alters the transcription of relatively few genes, the most unregulated being the transcription factor ETV1. These data suggest that proteolysis, tyrosine phosphorylation and translocation of dystroglycan to the nucleus resulting in altered gene transcription could be important mechanisms in the progression of prostate cancer.

Kubota D, Yoshida A, Tsuda H, et al.
Gene expression network analysis of ETV1 reveals KCTD10 as a novel prognostic biomarker in gastrointestinal stromal tumor.
PLoS One. 2013; 8(8):e73896 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
BACKGROUND: Prognostic biomarkers are required for risk stratification therapy in the patients with gastrointestinal stromal tumor (GIST). In this study, we aimed to identify prognostic biomarkers in GIST. We assessed the prognostic value of E twenty-six variant 1 (ETV1), a recently identified transcription factor unique to GIST. We also examined the clinical utility and functions of its downstream gene, potassium channel tetramerization domain containing protein 10 (KCTD10).
METHODS: The levels of ETV1 and KCTD10 were evaluated immunohistochemically in 112 patients with GIST treated at two hospitals. The functional properties of KCTD10 were examined by gene silencing assay in cultured GIST cells.
RESULTS: Immunohistochemistry revealed that ETV1 expression in GIST had no prognostic significance. In contrast, the disease-free survival rate was 88.5% in patients with KCTD10-positive tumors and 55.8% in those with KCTD10-negative tumors (p <0.0001). KCTD10 was an independent prognostic factor (p <0.05). In the low-risk classification group, KCTD10 was significantly associated with favorable prognosis (p = 0.0008). Gene silencing of KCTD10 increased cell proliferation and invasion, suggesting that KCTD10 has a tumor-suppressive function.
CONCLUSIONS: The GIST-specific transcription factor ETV1 may have no prognostic potential, whereas its downstream gene KCTD10 is associated with a favorable prognosis. Our study indicated the novel prognostic utility of KCTD10 in GIST, and suggested its tumor-suppressive effects on GIST cells. Further validation studies of KCTD10 for clinical applications, and functional verification of KCTD10 for better understanding of molecular basis of malignant phenotypes are worth challenging in GIST.

Gits CM, van Kuijk PF, Jonkers MB, et al.
MiR-17-92 and miR-221/222 cluster members target KIT and ETV1 in human gastrointestinal stromal tumours.
Br J Cancer. 2013; 109(6):1625-35 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
BACKGROUND: Gastrointestinal stromal tumours (GIST) are characterised by high expression of KIT and ETV1, which cooperate in GIST oncogenesis. Our aim was to identify microRNAs that are deregulated in GIST, have a role in GIST pathogenesis, and could potentially be used as therapeutic tool.
METHODS: Differentially expressed microRNAs between primary GIST (n=50) and gastrointestinal leiomyosarcomas (GI-LMS, n=10) were determined using microarrays. Selected microRNA mimics were transfected into GIST-882 and GIST-T1 cell lines to study the effects of microRNA overexpression on GIST cells. Luciferase reporter assays were used to establish regulation of target genes by selected microRNAs.
RESULTS: MiR-17-92 and miR-221/222 cluster members were significantly (P<0.01) lower expressed in GIST vs GI-LMS and normal gastrointestinal control tissues. MiR-17/20a/222 overexpression in GIST cell lines severely inhibited cell proliferation, affected cell cycle progression, induced apoptosis and strongly downregulated protein and--to a lesser extent--mRNA levels of their predicted target genes KIT and ETV1. Luciferase reporter assays confirmed direct regulation of KIT and ETV1 by miR-222 and miR-17/20a, respectively.
CONCLUSION: MicroRNAs that may have an essential role in GIST pathogenesis were identified, in particular miR-17/20a/222 that target KIT and ETV1. Delivering these microRNAs therapeutically could hold great potential for GIST management, especially in imatinib-resistant disease.

Chen Y, Chi P, Rockowitz S, et al.
ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss.
Nat Med. 2013; 19(8):1023-9 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Studies of ETS-mediated prostate oncogenesis have been hampered by a lack of suitable experimental systems. Here we describe a new conditional mouse model that shows robust, homogenous ERG expression throughout the prostate. When combined with homozygous Pten loss, the mice developed accelerated, highly penetrant invasive prostate cancer. In mouse prostate tissue, ERG markedly increased androgen receptor (AR) binding. Robust ERG-mediated transcriptional changes, observed only in the setting of Pten loss, included the restoration of AR transcriptional output and upregulation of genes involved in cell death, migration, inflammation and angiogenesis. Similarly, ETS variant 1 (ETV1) positively regulated the AR cistrome and transcriptional output in ETV1-translocated, PTEN-deficient human prostate cancer cells. In two large clinical cohorts, expression of ERG and ETV1 correlated with higher AR transcriptional output in PTEN-deficient prostate cancer specimens. We propose that ETS factors cause prostate-specific transformation by altering the AR cistrome, priming the prostate epithelium to respond to aberrant upstream signals such as PTEN loss.

Barros-Silva JD, Paulo P, Bakken AC, et al.
Novel 5' fusion partners of ETV1 and ETV4 in prostate cancer.
Neoplasia. 2013; 15(7):720-6 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Gene fusions involving the erythroblast transformation-specific (ETS) transcription factors ERG, ETV1, ETV4, ETV5, and FLI1 are a common feature of prostate carcinomas (PCas). The most common upstream fusion partner described is the androgen-regulated prostate-specific gene TMPRSS2, most frequently with ERG, but additional 5' fusion partners have been described. We performed 5' rapid amplification of cDNA ends in 18 PCas with ETV1, ETV4, or ETV5 outlier expression to identify the 5' fusion partners. We also evaluated the exon-level expression profile of these ETS genes in 14 cases. We identified and confirmed by fluorescent in situ hybridization (FISH) and reverse transcription-polymerase chain reaction the two novel chimeric genes OR51E2-ETV1 and UBTF-ETV4 in two PCas. OR51E2 encodes a G-protein-coupled receptor that is overexpressed in PCas, whereas UBTF is a ubiquitously expressed gene encoding an HMG-box DNA-binding protein involved in ribosome biogenesis. We additionally describe two novel gene fusion combinations of previously described genes, namely, SLC45A3-ETV4 and HERVK17-ETV4. Finally, we found one PCa with TMPRSS2-ETV1, one with C15orf21-ETV1, one with EST14-ETV1, and two with 14q133-q21.1-ETV1. In nine PCas (eight ETV1 and one ETV5), exhibiting ETS outlier expression and genomic rearrangement detected by FISH, no 5' fusion partner was found. Our findings contribute significantly to characterize the heterogeneous group of ETS gene fusions and indicate that all genes described as 5' fusion partners with one ETS gene can most likely be rearranged with any of the other ETS genes involved in prostate carcinogenesis.

Kiaii S, Clear AJ, Ramsay AG, et al.
Follicular lymphoma cells induce changes in T-cell gene expression and function: potential impact on survival and risk of transformation.
J Clin Oncol. 2013; 31(21):2654-61 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
PURPOSE: Previous studies have demonstrated the prognostic importance of the immune microenvironment in follicular lymphoma (FL). To investigate the molecular mechanisms during which tumor-infiltrating T cells (TILs) are altered in the FL microenvironment, we studied highly purified CD4 and CD8 TILs from lymph node biopsies at diagnosis in treatment-naive patients with FL compared with reactive tonsils and the peripheral blood of healthy donors.
PATIENTS AND METHODS: Gene expression profiling of highly purified CD4 and CD8 TILs was performed on the Affymetrix platform. Diagnostic tissue microarrays from an independent patient set (n = 172) were used to verify protein expression and analyze any impact of TIL-expressed genes on outcome. Time-lapse imaging was used to assess T-cell motility.
RESULTS: The most upregulated genes in both CD4 and CD8 TILs were PMCH, ETV1, and TNFRSF9. PMCH is not expressed in peripheral blood T cells, but expression is highly induced on culture with FL. Both CD4 and CD8 TILs from patients with FL have significantly impaired motility compared with those of healthy TILs from reactive tonsils and this can be induced on healthy T cells by FL cells. During multivariate analysis, a model incorporating the number and location of T cells expressing PMCH, NAMPT, and ETV1 showed prognostic significance for overall survival and for time to transformation.
CONCLUSION: We showed altered gene expression in TILs in FL and demonstrated that altering the immune microenvironment in FL affects overall survival and time to transformation in this disease.

Oh S, Shin S, Lightfoot SA, Janknecht R
14-3-3 proteins modulate the ETS transcription factor ETV1 in prostate cancer.
Cancer Res. 2013; 73(16):5110-9 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Overexpression of the ETS-related transcription factor ETV1 can initiate neoplastic transformation of the prostate. ETV1 activity is highly regulated by phosphorylation, but the underlying mechanisms are unknown. Here we report that all 14-3-3 proteins, with the exception of the tumor suppressor 14-3-3σ, can bind to ETV1 in a condition manner dictated by its prominent phosphorylation site S216. Non-σ 14-3-3 proteins synergized with ETV1 to activate transcription of its target genes MMP-1 and MMP-7, which regulate extracellular matrix in the prostate tumor microenvironment. S216 mutation or 14-3-3τ downregulation was sufficient to reduce ETV1 protein levels in prostate cancer cells, indicating that non-σ 14-3-3 proteins protect ETV1 from degradation. Notably, S216 mutation also decreased ETV1-dependent migration and invasion in benign prostate cells. Downregulation of 14-3-3τ reduced prostate cancer cell invasion and growth in the same manner as ETV1 attenuation. Finally, we showed that 14-3-3τ and 14-3-3ε were overexpressed in human prostate tumors. Taken together, our results showed that non-σ 14-3-3 proteins are important modulators of ETV1 function that promote prostate tumorigenesis.

Matullo G, Guarrera S, Betti M, et al.
Genetic variants associated with increased risk of malignant pleural mesothelioma: a genome-wide association study.
PLoS One. 2013; 8(4):e61253 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, only 5-17% of those exposed to asbestos develop MPM, suggesting the involvement of other environmental and genetic risk factors. To identify the genetic risk factors that may contribute to the development of MPM, we conducted a genome-wide association study (GWAS; 370,000 genotyped SNPs, 5 million imputed SNPs) in Italy, among 407 MPM cases and 389 controls with a complete history of asbestos exposure. A replication study was also undertaken and included 428 MPM cases and 1269 controls from Australia. Although no single marker reached the genome-wide significance threshold, several associations were supported by haplotype-, chromosomal region-, gene- and gene-ontology process-based analyses. Most of these SNPs were located in regions reported to harbor aberrant alterations in mesothelioma (SLC7A14, THRB, CEBP350, ADAMTS2, ETV1, PVT1 and MMP14 genes), causing at most a 2-3-fold increase in MPM risk. The Australian replication study showed significant associations in five of these chromosomal regions (3q26.2, 4q32.1, 7p22.2, 14q11.2, 15q14). Multivariate analysis suggested an independent contribution of 10 genetic variants, with an Area Under the ROC Curve (AUC) of 0.76 when only exposure and covariates were included in the model, and of 0.86 when the genetic component was also included, with a substantial increase of asbestos exposure risk estimation (odds ratio, OR: 45.28, 95% confidence interval, CI: 21.52-95.28). These results showed that genetic risk factors may play an additional role in the development of MPM, and that these should be taken into account to better estimate individual MPM risk in individuals who have been exposed to asbestos.

Smit FP, Salagierski M, Jannink S, Schalken JA
High-resolution ERG-expression profiling on GeneChip exon 1.0 ST arrays in primary and castration-resistant prostate cancer.
BJU Int. 2013; 111(5):836-42 [PubMed] Related Publications
OBJECTIVE: To assess whether oestrogen-regulated gene (ERG) expression analysis using GeneChip arrays can predict transmembrane protease, serine 2 (TMPRSS2)-ERG fusion. The expression level of the TMPRSS2-ERG gene was studied in various histological grades of prostate cancer and castration-resistant prostate cancer (CPRC).
PATIENTS AND METHODS: GeneChip Affymetrix exon 1.0 ST arrays were used for expression profiling of ERG, erythroblast transformation-specific (ETS) variant gene 1 (ETV1), ETV4 and ETV5 genes in 67 prostate cancer tissue specimens. Real-time quantitative polymerase chain reaction analysis and in some cases DNA sequencing was used to validate the presence and the expression levels of TMPRSS2-ERG gene fusions.
RESULTS: In our series of patients with prostate cancer over expression of the ERG gene predicted the presence of TMPRSS2-ERG rearrangements in almost all cases. ETS expression by itself outmatched the diagnostic performance of the ERG exons ratioing allowing equal detection of the less frequent ETS gene fusion transcripts. The gene fusions were expressed at significantly lower levels in CPRC but occurred more frequently than in primary prostate cancer.
CONCLUSIONS: ERG expression analysis using GeneChip arrays appears to be an excellent diagnostic tool for identifying gene rearrangements. In coming years, measuring expression of the ETS gene family by itself might become a clinically relevant surrogate test to identify patients with fusion-positive prostate cancer. The variation of gene fusion expression levels, particularly in CPRC, needs to be taken into account when using quantitative molecular diagnosis of prostate cancer.

Kacprzyk LA, Laible M, Andrasiuk T, et al.
ERG induces epigenetic activation of Tudor domain-containing protein 1 (TDRD1) in ERG rearrangement-positive prostate cancer.
PLoS One. 2013; 8(3):e59976 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
BACKGROUND: Overexpression of ERG transcription factor due to genomic ERG-rearrangements defines a separate molecular subtype of prostate tumors. One of the consequences of ERG accumulation is modulation of the cell's gene expression profile. Tudor domain-containing protein 1 gene (TDRD1) was reported to be differentially expressed between TMPRSS2:ERG-negative and TMPRSS2:ERG-positive prostate cancer. The aim of our study was to provide a mechanistic explanation for the transcriptional activation of TDRD1 in ERG rearrangement-positive prostate tumors.
METHODOLOGY/PRINCIPAL FINDINGS: Gene expression measurements by real-time quantitative PCR revealed a remarkable co-expression of TDRD1 and ERG (r(2) = 0.77) but not ETV1 (r(2)<0.01) in human prostate cancer in vivo. DNA methylation analysis by MeDIP-Seq and bisulfite sequencing showed that TDRD1 expression is inversely correlated with DNA methylation at the TDRD1 promoter in vitro and in vivo (ρ = -0.57). Accordingly, demethylation of the TDRD1 promoter in TMPRSS2:ERG-negative prostate cancer cells by DNA methyltransferase inhibitors resulted in TDRD1 induction. By manipulation of ERG dosage through gene silencing and forced expression we show that ERG governs loss of DNA methylation at the TDRD1 promoter-associated CpG island, leading to TDRD1 overexpression.
CONCLUSIONS/SIGNIFICANCE: We demonstrate that ERG is capable of disrupting a tissue-specific DNA methylation pattern at the TDRD1 promoter. As a result, TDRD1 becomes transcriptionally activated in TMPRSS2:ERG-positive prostate cancer. Given the prevalence of ERG fusions, TDRD1 overexpression is a common alteration in human prostate cancer which may be exploited for diagnostic or therapeutic procedures.

Baena E, Shao Z, Linn DE, et al.
ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients.
Genes Dev. 2013; 27(6):683-98 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Distinguishing aggressive from indolent disease and developing effective therapy for advanced disease are the major challenges in prostate cancer research. Chromosomal rearrangements involving ETS transcription factors, such as ERG and ETV1, occur frequently in prostate cancer. How they contribute to tumorigenesis and whether they play similar or distinct in vivo roles remain elusive. Here we show that in mice with ERG or ETV1 targeted to the endogenous Tmprss2 locus, either factor cooperated with loss of a single copy of Pten, leading to localized cancer, but only ETV1 appeared to support development of invasive adenocarcinoma under the background of full Pten loss. Mechanistic studies demonstrated that ERG and ETV1 control a common transcriptional network but largely in an opposing fashion. In particular, while ERG negatively regulates the androgen receptor (AR) transcriptional program, ETV1 cooperates with AR signaling by favoring activation of the AR transcriptional program. Furthermore, we found that ETV1 expression, but not that of ERG, promotes autonomous testosterone production. Last, we confirmed the association of an ETV1 expression signature with aggressive disease and poorer outcome in patient data. The distinct biology of ETV1-associated prostate cancer suggests that this disease class may require new therapies directed to underlying programs controlled by ETV1.

Boormans JL, Korsten H, Ziel-van der Made AJ, et al.
Identification of TDRD1 as a direct target gene of ERG in primary prostate cancer.
Int J Cancer. 2013; 133(2):335-45 [PubMed] Related Publications
Molecular classification of ERG-rearranged prostate cancer clarifies the role of TMPRSS2-ERG in the development and progression of prostate cancer. The objective of our study was to identify direct ERG target genes in ERG-rearranged prostate cancer. Two independent cohorts of primary prostate cancer (Cohort A, n=48; Cohort B, n=31), a cohort of late-stage prostate cancer (n=51) and expression array data of a cohort of primary prostate tumors from a different institute (n=128) were analyzed for expression of genes that were coexpressed with ERG overexpression. By genome-wide expression analysis and Q-RT-PCR it was shown that the gene Tudor domain containing 1 (TDRD1) was by far the strongest correlated gene with ERG overexpression in both Cohort A and B. Expression array analysis of the patient cohort from a different institute showed a large overlap in genes that were positively correlated with ERG overexpression, including TDRD1. In late-stage prostate cancer, TDRD1 was also coexpressed with ERG overexpression, although a proportion of ERG-negative late-stage samples expressed TDRD1. TDRD1 expression was not associated with ETV1 overexpression. In the prostate cancer cell line VCaP, downregulation of ERG by shRNA lead to a lower expression level of TDRD1 and resulted in a decreased activity of the TDRD1 promoter. By mutation analysis we identified a functional ERG binding site in the TDRD1 promoter. Our findings show TDRD1 as the first identified upregulated direct ERG target gene that is strongly associated with ERG overexpression in primary prostate cancer.

Xie L, Gazin C, Park SM, et al.
A synthetic interaction screen identifies factors selectively required for proliferation and TERT transcription in p53-deficient human cancer cells.
PLoS Genet. 2012; 8(12):e1003151 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Numerous genetic and epigenetic alterations render cancer cells selectively dependent on specific genes and regulatory pathways, and represent potential vulnerabilities that can be therapeutically exploited. Here we describe an RNA interference (RNAi)-based synthetic interaction screen to identify genes preferentially required for proliferation of p53-deficient (p53-) human cancer cells. We find that compared to p53-competent (p53+) human cancer cell lines, diverse p53- human cancer cell lines are preferentially sensitive to loss of the transcription factor ETV1 and the DNA damage kinase ATR. In p53- cells, RNAi-mediated knockdown of ETV1 or ATR results in decreased expression of the telomerase catalytic subunit TERT leading to growth arrest, which can be reversed by ectopic TERT expression. Chromatin immunoprecipitation analysis reveals that ETV1 binds to a region downstream of the TERT transcriptional start-site in p53- but not p53+ cells. We find that the role of ATR is to phosphorylate and thereby stabilize ETV1. Our collective results identify a regulatory pathway involving ETV1, ATR, and TERT that is preferentially important for proliferation of diverse p53- cancer cells.

Wang JJ, Liu YX, Wang W, et al.
Fusion between TMPRSS2 and ETS family members (ERG, ETV1, ETV4) in prostate cancers from northern China.
Asian Pac J Cancer Prev. 2012; 13(10):4935-8 [PubMed] Related Publications
In this study we evaluated the frequency of fusion between TMPRSS2 and ETS family members (ERG, ETV1, ETV4) in prostate cancers in patients from northern China in order to explore differences in fusion rates among regions in northern and southern China, other parts of Asia, Europe, and North America. We examined 100 prostate cancer patients, diagnosed by means of prostate biopsy; fluorescence in situ hybridization (FISH) was used to detect the expression of TMPRSS2, ERG, ETV1 and ETV4 in cancer tissue. Differences in gene fusion rates among different ethnics groups were also analyzed. Of the 100 prostate cancer patients, 55 (55%) had the fusion gene. Among the patients with the fusion gene, 46 (83.6%) patients had the TMPRSS2:ERG fusion product, 8 (14.8%) patients had TMPRSS2:ETV1 fusion, 1 (1.6%) patient had TMPRSS2:ETV4.

Shin S, Oh S, An S, Janknecht R
ETS variant 1 regulates matrix metalloproteinase-7 transcription in LNCaP prostate cancer cells.
Oncol Rep. 2013; 29(1):306-14 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Prostate cancer is characterized by the recurrent translocation of ETS transcription factors, including ETS variant 1 (ETV1) [also known as ETS-related 81 (ER81)]. Transgenic ETV1 mice develop prostatic intraepithelial neoplasia, yet the mechanisms by which ETV1 exerts its deleterious function remain largely unexplored. In this study, we demonstrated that ETV1 is capable of binding to the matrix metalloproteinase-7 (MMP-7) gene promoter both in vitro and in vivo. ETV1 stimulated the activity of the MMP-7 promoter, which was suppressed upon mutation of two ETV1 binding sites located within 200 base pairs upstream of the MMP-7 transcription start site. ETV1 overexpression in human LNCaP prostate cancer cells induced endogenous MMP-7 gene transcription, whereas ETV1 downregulation had the opposite effect. While MMP-7 overexpression did not influence LNCaP cell proliferation, it increased cell migration, which may be important during later stages of tumorigenesis. Finally, MMP-7 mRNA was significantly overexpressed in human prostate tumors compared to normal tissue. Together, these results showed that MMP-7 is a bona fide ETV1 target gene, implicating that MMP-7 upregulation is partially responsible for the oncogenic effects of ETV1 in the prostate.

Paulo P, Ribeiro FR, Santos J, et al.
Molecular subtyping of primary prostate cancer reveals specific and shared target genes of different ETS rearrangements.
Neoplasia. 2012; 14(7):600-11 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
This work aimed to evaluate whether ETS transcription factors frequently involved in rearrangements in prostate carcinomas (PCa), namely ERG and ETV1, regulate specific or shared target genes. We performed differential expression analysis on nine normal prostate tissues and 50 PCa enriched for different ETS rearrangements using exon-level expression microarrays, followed by in vitro validation using cell line models. We found specific deregulation of 57 genes in ERG-positive PCa and 15 genes in ETV1-positive PCa, whereas deregulation of 27 genes was shared in both tumor subtypes. We further showed that the expression of seven tumor-associated ERG target genes (PLA1A, CACNA1D, ATP8A2, HLA-DMB, PDE3B, TDRD1, and TMBIM1) and two tumor-associated ETV1 target genes (FKBP10 and GLYATL2) was significantly affected by specific ETS silencing in VCaP and LNCaP cell line models, respectively, whereas the expression of three candidate ERG and ETV1 shared targets (GRPR, KCNH8, and TMEM45B) was significantly affected by silencing of either ETS. Interestingly, we demonstrate that the expression of TDRD1, the topmost overexpressed gene of our list of ERG-specific candidate targets, is inversely correlated with the methylation levels of a CpG island found at -66 bp of the transcription start site in PCa and that TDRD1 expression is regulated by direct binding of ERG to the CpG island in VCaP cells. We conclude that ETS transcription factors regulate specific and shared target genes and that TDRD1, FKBP10, and GRPR are promising therapeutic targets and can serve as diagnostic markers for molecular subtypes of PCa harboring specific fusion gene rearrangements.

Chen Y, Zou H, Yang LY, et al.
ER81-shRNA inhibits growth of triple-negative human breast cancer cell line MDA-MB-231 in vivo and in vitro.
Asian Pac J Cancer Prev. 2012; 13(5):2385-92 [PubMed] Related Publications
The lack of effective treatment targets for triple-negative breast cancers make them unfitted for endocrine or HER2 targeted therapy, and their prognosis is poor. Transcription factor ER81, a downstream gene of the HER2, is highly expressed in breast cancer lines, breast atypical hyperplasia and primary breast cancers including triple-negative examples. However, whether and how ER81 affects breast cancer carcinogenesis have remained elusive. We here assessed influence on a triple-negative cell line. ER81-shRNA was employed to silence ER81 expression in the MDA-MB-231 cell line, and MTT, colony-forming assays, and flow cytometry were used to detect cell proliferation, colony-forming capability, cell cycle distribution, and cell apoptosis in vitro. MDA-MB-231 cells stably transfected with ER81-shRNA were inoculated into nude mice, and growth inhibition of the cells was observed in vivo. We found that ER81 mRNA and protein expression in MDA-MB-231 cells was noticeably reduced by ER81-shRNA, and that cell proliferation and clonality were decreased significantly. ER81-shRNA further increased cell apoptosis and the residence time in G0/G1 phase, while delaying tumor-formation and growth rate in nude mice. It is concluded that ER81 may play an important role in the progression of breast cancer and may be a potentially valuable target for therapy, especially for triple negative breast cancer.

Shaikhibrahim Z, Braun M, Nikolov P, et al.
Rearrangement of the ETS genes ETV-1, ETV-4, ETV-5, and ELK-4 is a clonal event during prostate cancer progression.
Hum Pathol. 2012; 43(11):1910-6 [PubMed] Related Publications
ETS gene rearrangements are frequently found in prostate cancer. Several studies have assessed the rearrangement status of the most commonly found ETS rearranged gene ERG, and the less frequent genes, ETV-1, ETV-4, ETV-5, and ELK-4 in primary prostate cancer. However, frequency in metastatic disease is not well investigated. Recently, we have assessed the ERG rearrangement status in both primary and corresponding lymph node metastases and observed that ERG rearrangement in primary prostate cancer transfers into lymph node metastases, suggesting it to be a clonal expansion event during prostate cancer progression. As a continuation, we investigated in this study whether this observation is valid for the less frequent ETS rearranged genes. Using dual-color break-apart fluorescent in situ hybridization assays, we evaluated the status of all less frequent ETS gene rearrangements for the first time on tissue microarrays constructed from a large cohort of 86 patients with prostate cancer and composed of primary and corresponding lymph node metastases, as well as in a second cohort composed of 43 distant metastases. ETV-1, ETV-4, ETV-5, and ELK-4 rearrangements were found in 8 (10%) of 81, 5 (6%) of 85, 1 (1%) of 85, and 2 (2%) of 86 of primary prostate cancer, respectively, and in 6 (8%) of 73, 4 (6%) of 72, 1 (1%) of 75, and 1 (1%) of 78 of corresponding lymph node metastases, respectively. ETV-1 and ETV-5 rearrangements were not found in the distant metastases cases, whereas ETV-4 and ELK-4 rearrangements were found in 1 (4%) of 25 and 1 (4%) of 24, respectively. Our findings suggest that rearrangement of the less frequent ETS genes is a clonal event during prostate cancer progression.

Shulman SC, Katzenstein H, Bridge J, et al.
Ewing sarcoma with 7;22 translocation: three new cases and clinicopathological characterization.
Fetal Pediatr Pathol. 2012; 31(6):341-8 [PubMed] Related Publications
Ewing sarcoma (ES) is the second most common primary bone malignancy in children and is typically characterized by a translocation involving the EWS gene on chromosome 22 and a member of the ETS family of genes: FLI1 (90%), ERG1 (5%), ETV1 (1%), ETV4 (1%), and FEV (1%). We identified three new cases of t(7;22) (p22;q12) (EWS-ETV1) ES and a literature search revealed an additional six cases. In comparison to conventional ES with t(11;22) (q24;q12) (EWS-FLI1), the t(7;22) ES variant has a higher propensity for females and children in a younger age group and it occurs more commonly in extraosseous locations.

Oh S, Shin S, Janknecht R
ETV1, 4 and 5: an oncogenic subfamily of ETS transcription factors.
Biochim Biophys Acta. 2012; 1826(1):1-12 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
The homologous ETV1, ETV4 and ETV5 proteins form the PEA3 subfamily of ETS transcription factors. In Ewing tumors, chromosomal translocations affecting ETV1 or ETV4 are an underlying cause of carcinogenesis. Likewise, chromosomal rearrangements of the ETV1, ETV4 or ETV5 gene occur in prostate tumors and are thought to be one of the major driving forces in the genesis of prostate cancer. In addition, these three ETS proteins are implicated in melanomas, breast and other types of cancer. Complex posttranslational modifications govern the activity of PEA3 factors, which can promote cell proliferation, motility and invasion. Here, we review evidence for a role of ETV1, 4 and 5 as oncoproteins and describe modes of their action. Modulation of their activation or interaction with cofactors as well as inhibiting crucial target gene products may ultimately be exploited to treat various cancers that are dependent on the PEA3 group of ETS transcription factors.

Birner P, Beer A, Vinatzer U, et al.
MAPKAP kinase 2 overexpression influences prognosis in gastrointestinal stromal tumors and associates with copy number variations on chromosome 1 and expression of p38 MAP kinase and ETV1.
Clin Cancer Res. 2012; 18(7):1879-87 [PubMed] Related Publications
PURPOSE: ETV1 has been proposed to be activated by KIT mutations in gastrointestinal stromal tumors (GIST). The aim of the study was to evaluate the clinical role of ETV1 and associated proteins in GIST.
EXPERIMENTAL DESIGN: Expressions of ETV1, MAPKAP kinase 2 (MAPKAPK2), phosphorylated p38 MAP kinase (pp38), phosphorylated MSK1 (pMSK1), phosphorylated RSK1, COP1, and KIT protein were determined immunohistochemically in 139 GISTs. Sequence analysis of KIT, PDGFRA, and MAPKAPK2 and FISHs of ETV1 as well as chromosomes 1 and 7 were done.
RESULTS: Prominent ETV1 expression was seen in 50% of GISTs, but no correlation with clinical outcome was found. Correlation of ETV1 expression and KIT mutation was seen in 60% of cases. MAPKAPK2 overexpression (n = 62/44.6%) correlated with pp38 expression (P = 0.021, χ(2) test) and alterations of chromosome 1 (n = 17, P = 0.024, χ(2) test). In one of 20 sequenced cases with high MAKAPK2 expression, a putative damaging MAPKAPK2 gene mutation was found. All relapsing GISTs with very low/low risk according to Fletcher showed high MAPKAPK2 and KIT expression. MAPKAPK2 overexpression was an independent prognostic factor for disease-free survival (P = 0.006, Cox regression).
CONCLUSION: ETV1 is not universally overexpressed in GIST and seems to also be induced by pathways other than KIT mutation. Nevertheless, its clinical relevance is low. Overexpression of ETV1 inhibitor MAPKAPK2 is associated with shorter survival in GIST, indicating a clinically relevant role of this gene not reported previously. Patients with low-risk GISTs showing MAPKAPK2 overexpression might profit from early adjuvant tyrosine kinase inhibitor therapy.

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