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Gene Section
Review
ETV1 (ets variant 1)
Yu Chen, Ping Chi
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 1275 York, Avenue,
New York, NY 10065, USA (YC, PC)
Published in Atlas Database: February 2013
Online updated version : http://AtlasGeneticsOncology.org/Genes/ETV1ID73ch7p21.html
DOI: 10.4267/2042/51046
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Expression
Identity
ETV1 has 7 Refseq transcripts that are generated by
alternative splicing and alternative transcriptional
initiation.
The ETV1 protein is physiologically expressed in the
central nervous system including the developing
propioceptive neurons, the motor neurons and the
dopaminergic neurons (Arber et al., 2000; Flames and
Hobert, 2009).
ETV1 is also expressed in the inner core cells of the
Pacinian corpuscle (Sedy et al., 2006) and in the
interstitial cells of Cajal (Chen et al., 2007; Chi et al.,
2010).
Pathologically, the ETV1 protein is aberrantly
expressed in a subset of melanoma and prostate cancer
through genomic rearrangements (Jané-Valbuena et al.,
2010; Tomlins et al., 2005), or abnormally highly
expressed in gastrointestinal stromal tumor (GIST)
through high endogenous expression and protein
stabilization by active MAP kinase signaling (Chi et al.,
2010), or partially highly expressed as part of an
oncogenic fusion protein-EWSR1-ETV1-in Ewing
sarcoma (Jeon et al., 1995).
Pseudogene
Localisation
No pseudogene reported.
Nucleus.
Protein
Function
Other names: ER81
HGNC (Hugo): ETV1
Location: 7p21.2
DNA/RNA
Description
The ETV1 (ETS-translocation variant 1) gene belongs
to the PEA3-subfamily of erythroblast transformationspecific (ETS)-family of transcription factors.
It is located on chromosome 7p21.3, consisting of 13
exons and spanning approximately 100 kb DNA in
length (Coutte et al., 1999).
Transcription
ETV1 belongs to the ETS (E-twenty-six) family of
transcription factors and the PEA3 subfamily
transcription factors (ETV1, ETV4 and ETV5).
It specifically recognizes the GGAA core consensus
DNA motif in the genome and mediates transcriptional
activation and repression of target genes in cell type
and cell lineage-specific contexts.
Description
ETV1 belongs to the PEA3-subfamily of erythroblast
transformation-specific (ETS)-family of transcription
factors. There are 7 protein isoforms of ETV1, ranging
from 374 amino acids to 477 amino acids (~55 kD).
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(7)
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ETV1 (ets variant 1)
Chen Y, Chi P
The ETV1 gene locus is on the p arm of chromosome 7 (7p21.3), spanning from 13930854 to 14031050 (Feb. 2009 GRCh37/hg19).
Schematics of ETV1 and PEA3-subfamily homolog, ETV4 and ETV5. Transcriptional activation acidic domains are in grey and ETS DNA
binding domains are in black (adapted from Oh et al., 2012).
ETV1 is critical in the normal development of a
functional sensory-motor circuitry in the spinal cord
(Arber et al., 2000), the specification of a group of
specialized dopaminergic neurons in the central
nervous system (Flames and Hobert, 2009), the normal
development of the Pacinian corpuscle (Sedy et al.,
2006), and the normal development and specification of
the subclasses of interstitial cells of Cajal localized in
the circular muscle and in the myenteric plexus (Chi et
al., 2010).
ETV1 contributes to the pathogenesis of a number of
cancer types through 1) aberrantly overexpression in
melanoma and prostate cancer via genomic
rearrangement (Jané-Valbuena et al., 2010; Tomlins et
al., 2007; Tomlins et al., 2005), 2) abnormal protein
stabilization in GIST (Chi et al., 2010), 3) formation of
the oncogenic fusion protein EWSR1-ETV1 in Ewing
sarcoma (Jeon et al., 1995).
Mutations
Note
No validated known mutations.
Implicated in
Ewing sarcoma
Prognosis
The prognostic relevance remains to be determined.
Cytogenetics
Ewing sarcoma translocation, t(7;22)(p22;q12) that
fused EWSR1 to the ETV1 gene (Jeon et al., 1995).
Hybrid/Mutated gene
EWSR1-ETV1 fusion gene accounts for ~1% of all
Ewing sarcomas. The majority of Ewing sarcoma
fusion genes are EWSR1-FLI1 (~85%) and EWSR1ERG (~10%).
Abnormal protein
EWSR1-ETV1 fusion protein that fuses the first 7
exons of EWSR1 to the last 3-4 exons of ETV1 (exons
10 or 11-exon 13).
Homology
A member of the ETS-family transcription factor and
the PEA3 subfamily transcription factors , with most
sequence homology to ETV5 and ETV4.
Common breakpoints of the EWS-ETV1 fusion. DNA-BD: DNA binding domain; Pro: proline-rich activation domain; PTD: pointed domain;
RGG: arginine-glycine-glycine-rich region; RRM: RNA recognition motif; SYQG: serine-tyrosine-glutamine-glycine-rich region that has a
high transactivation potential; ZN: zinc finger. Adapted from Janknecht, 2005.
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(7)
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ETV1 (ets variant 1)
Chen Y, Chi P
Typical breakpoint in prostate cancer fusions.
Oncogenesis
ETV1 is amplified in 13% of primary and 18% of
metastatic melanomas, which results in aberrant
overexpression. ETV1 is required for growth and
proliferation of melanoma cells with ETV1
amplification and it cooperates with oncogenic NRAS
(G12D) for tumorigenesis in mice (Jané-Valbuena et
al., 2010).
Oncogenesis
The EWSR1-ETS (EWSR1-FLI1, EWSR1-ETV1,
EWSR1-ERG, etc) fusion proteins are thought to be the
"oncogenic drivers" in Ewing sarcoma. EWSR1-FLI1
and EWSR1-ERG have been modeled in cell lines
demonstrating the requirement of the oncogenic fusion
proteins for Ewing sarcoma cell line growth and
survival.
The EWSR1-ETV1 fusion protein has not been
modeled.
Gastrointestinal stromal tumor (GIST)
Prognosis
The prognostic relevance remains to be determined.
Oncogenesis
ETV1 is naturally highly expressed and is required for
the development of the interstitial cells of Cajal (ICCs)
in the gastrointestinal tract that are the precursor cells
of GIST. It is also highly expressed and required for the
growth, survival and tumorigenesis of GISTs. It drives
a core transcriptional program that is conserved in ICC
and GIST. ETV1 protein level is stabilized by active
KIT and downstream MAP kinase signaling pathways
and cooperates with mutant KIT in GIST pathogenesis
(Chi et al., 2010).
Prostate cancer
Prognosis
ETV1 fusion seems to confer a poorer prognosis in
several studies.
Oncogenesis
ETV1 is aberrantly overexpressed in prostate cancer
through genomic rearrangements that result in
overexpression of a truncated ETV1 or full-length
ETV1.
ETV1 is required for the growth of ETV1-positive
prostate cancer cells and ETV1 overexpression confers
invasiveness prostate cancer cells (Tomlins et al., 2007;
Tomlins et al., 2005).
Breakpoints
Melanoma
See Figure below.
Prognosis
The prognostic relevance remains to be determined.
ETV1 and partners.
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ETV1 (ets variant 1)
Chen Y, Chi P
References
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This article should be referenced as such:
Chen Y, Chi P. ETV1 (ets variant 1). Atlas Genet Cytogenet
Oncol Haematol. 2013; 17(7):483-486.
Chen H, Ordög T, Chen J, Young DL, Bardsley MR, Redelman
D, Ward SM, Sanders KM. Differential gene expression in
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(7)
486