ERG (v-ets erythroblastosis virus E26 oncogene like (avian))

2010-11-01 Roopika Menon , Martin Braun , Sven Perner Affiliation

Identity

HGNC

ERG

LOCATION

21q22.2

IMAGE

LEGEND

Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

LOCUSID

2078

ALIAS

erg-3,p55

FUSION GENES

Show Gene Fusions

DNA/RNA

ERG gene locus on the q-arm of chromosome 21 (21q22.2) spanning from 39751949 to 40033704 (according to UCSC genome browser, Feb. 2009 GRCh37/hg19, and Ensemble, Aug. 2010).

Description

The ERG gene belongs to the erythroblast transformation-specific (ETS) family of transcriptions factors. The ERG gene (ETS related gene 1) is located on chromosome 21, and consists of 17 exons, approximately 300 kb DNA in length.

Transcription

The ERG gene forms 20 known transcripts (ranging from 560 to 5034 bp in length), amongst which 15 are coding for proteins, and 5 are non-coding. 8 alternative splice variants are known.

Pseudogene

No observed pseudogenes.

Proteins

Description

Amongst the 20 known transcripts of the ERG gene, 15 are protein coding. The 15 proteins range from 171 to 486 amino acids in length, and up to 55 kDa in weight.

Expression

On the protein level, ERG is mainly expressed in the nucleus and is rarely seen in the cytoplasm. Basically, in the GNF SymAtlas database, major ERG expression was found to be in CD34+ cells (that include both hematopoietic stem cells and endothelial cells). In detail, ERG is reported to be expressed during early T and B cell development, and down-regulated in later stages of B and T cell differentiation. Also, ERG is expressed in platelets, megakaryoblastic cell lines, primary megakaryoblastic leukemia (AMKL or M7-AML) in Down syndrome patients. Furthermore, ERG is strongly expressed in ERG gene rearranged prostate tissue (both in prostatic cancer tissue and adjacent prostatic intraepithelial neoplasia lesions). Of note, using immunohistochemistry, ERG expression is regularly observed in lymphocytes and small blood vessels.

Localisation

Predominantely nuclear and rarely cytoplasmic.

Function

The ERG protein is a member of the ETS-family and is known to bind to purine-rich sequences. ERG and other members of the same family are downstream regulators of mitogenic signal transduction pathways. They are key regulators of embryonic development, cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis. At the DNA level, isoforms of ERG are known to regulate methylation. Further, ERG is required for platelet adhesion to the subendothelium, inducing vascular cell remodeling. Moreover, hematopoesis, as well as the differentiation and maturation of megakaryocytic cells are regulated by ERG. Overexpression of the ERG protein is suggested to aid in forming solid tumors. However, the exact molecular mechanisms of ERG as a transcription factor are still unknown.

Homology

A member of the ETS transcription factors, most homologous to FLI1.

Mutations

Note

No known mutations.

Implicated in

Entity name

Ewings sarcoma

Prognosis

The prognostic relevance of an ERG gene fusion or an ERG overexpression in Ewings sarcoma (EWS-ETS fusion type) is yet to be determined. So far, no prognostic relevance could be shown.

Hybrid gene

If a gene fusion occurs in Ewings sarcoma, most frequently it is a fusion of EWS to FLI-1 (in app. 85% of cases) or ERG (in app. 10% of cases). Other ETS genes rarely serve as EWS gene fusion partners (in app. 5% of cases).

Fusion protein

The EWS gene fuses with the carboxyl terminal of ERG containing the ETS DNA binding domain of ERG. Therefore, the resulting fusion protein deregulates a large number of genes by so far poorly defined mechanisms.

Oncogenesis

In a transgenic mouse model expression of the EWS-ERG in lymphoid progenitors induced T-cell leukemia.

Entity name

Acute myeloid leukemia (AML)

Prognosis

Several studies suggest a poorer prognosis for FUS-ERG gene fusion positive AML as compared to non-fused AML. Moreover, an ERG overexpression, not necessarily due to the FUS-ERG gene fusion, predicts an increased relapse risk and shorter survival in AML patients. However, the exact contribution of ERG overexpression to myeloid leukemiogenesis and progression is still unknown.

Hybrid gene

In the FUS-ERG gene fusion, the FUS gene fuses with the carboxyl terminal of ERG containing the ETS DNA binding domain of ERG. Of note, in a single case, a gene fusion of ERG with the myeloid ELF-like factor 1 (ELF4) was detected.

Oncogenesis

The FUS-ERG fusion protein helps in activating the oncogenic activity of transcription factors.

Entity name

Prostate cancer

Prognosis

The body of literature is controversial about the prognostic relevance of ERG rearrangements in prostate cancer. Some studies reported an association of the ERG rearrangement with adverse clinical parameters (i.e. time to prostate cancer specific death and the development of hormone-refractory metastasis). On the other hand, some studies demonstrated an association of ERG rearrangement with parameters of more favourable outcome, such as lower Gleason score, stage, volume, better overall survival, or late biochemical recurrence. Interestingly, a subset of studies without any such association was reported as well.

Hybrid gene

In approximately 50% of prostate cancers, the ERG gene is rearranged, i.e. fused to another gene. In case of a rearrangement, TMPRSS2 is the ERG 5 fusion partner in the vast majority of cases (app. 85%). Other known, but rarely occurring ERG fusion partners include NDRG1, SLC45A3, and HERPUD1. The ERG gene rearrangement either occurs due to a deletion, or an insertion.

Schematic displaying ERG rearrangement status (via FISH) in prostate cancer. The red-labelled centromeric and the green-labelled telomeric probes span the ERG locus on chromosomes 21. If a break-apart occurs, the green signal is either lost (ERG rearrangement through deletion) or translocated (ERG rearrangement through insertion). An ERG break-apart as determined by FISH accounts for a fusion of ERG mainly with TMPRSS2 but also with other 5 fusion partners such as SLC45A3, HERPUD1, or NDRG1. A: Both alleles with wild type (wt) ERG. B: One allele with ERG rearrangement through deletion (single red signal) and the other allele with wt ERG (yellow signal). C: One allele with ERG rearrangement through insertion (separated red and green signal) and the other allele with wt ERG (yellow signal).

Fusion protein

An ERG gene rearrangement in prostate cancer mainly results in an androgen dependant ERG overexpression.

Oncogenesis

In-vitro models complement that over expression of truncated ERG and various TMPRSS2-ERG isoforms increase cell migration and invasion. In-vivo recapitulation of ETS fusions by prostate specific expression of truncated ERG in mice resulted in the development of PIN but not carcinoma. Subsequent work on transgenic TMPRSS2-ERG mice develop PIN progressing to invasive cancer, but only in the context of PI3-kinase pathway activation. TMPRSS2-ERG-positive human tumors are also enriched for PTEN loss, suggesting cooperation in prostate tumorigenesis.

Entity name

Acute lymphoblastic leukemia (ALL)

Prognosis

Overexpression of ERG was shown to be a risk factor in adult T-ALL. ALL patients with ERG overexpression were four times more likely to fail long-term recurrence free survival, indicating inferior survival.

Oncogenesis

Studies assessing ERG overexpression in ALL have shown that due to the involvement of ERG in T-cell development, it may have an oncogenic potential.

Entity name

Acute megakaryoblastic leukemia (AMKL)

Prognosis

Even though ERG is highly considered to be oncogenic in AMKL, no prognostic relevance has been determined.

Oncogenesis

ERG was found to be expressed megakaryoblastic leukemic cell lines and in primary leukemic cells from DS patients. Moreover, in mouse models, expression of ERG drove megakaryopoiesis and lead to a rapid development of aggressive leukemia.

Entity name

Alzheimers disease (AD)

Note

ERG has been linked to AD, due to an ERG protein overexpression as compared to control patients. This is further supported by experiments conducted on patients suffering from Down syndrome, who gradually develop AD-like symptoms, linked to ERG overexpression.

Entity name

Down syndrome (DS)

Note

DS is associated with trisomy of the chromosome 21, where the ERG gene is located. The trisomy is considered to be responsible for an ERG overexpression. In a DS mouse model, an induced functional disomy of the ERG allele corrects some pathologic features of the disease, including myeloproliferation and progenitor cell expansion, suggesting a pathogenic effect of trisomy driven ERG overexpression.

Entity name

ERG involvement in endothelial development

Note

ERG has been reported to regulate genes involved in chondrogenesis and angiogenesis and functions as a modulator of endothelial cell differentiation. In an in-vitro study, the decrease of the ERG protein follows a reduction in endothelial cell proliferation and vascular tube formation. In human umbilical vein endothelial cell lines, vascular endothelial growth factor (VEGF) was seen to significantly up-regulate ERG expression. Controversially, on the other hand, ERG expression was shown to inhibit responsiveness to the VEGF receptor in a Down Syndrome mouse model.

Entity name

ERG involvement in lymphoid development

Note

ERG was reported to be expressed in during early T and B cell development, and to be down-regulated in later stages of B and T cell differentiation. In detail, the ERG protein modulates the maturation of lymphoid cells. Interestingly, ERG overexpression is associated with T-ALL.

Breakpoints

Bibliography

Pubmed ID	Last Year	Title	Authors

Other Information

Locus ID:

NCBI: 2078
MIM: 165080
HGNC: 3446
Ensembl: ENSG00000157554

Variants:

dbSNP: 2078
ClinVar: 2078
TCGA: ENSG00000157554
COSMIC: ERG

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000157554	ENST00000288319	P11308
ENSG00000157554	ENST00000398897	P11308
ENSG00000157554	ENST00000398905	B5MDW0
ENSG00000157554	ENST00000398907	A8MX39
ENSG00000157554	ENST00000398910	A8MZ24
ENSG00000157554	ENST00000398911	P11308
ENSG00000157554	ENST00000398919	P11308
ENSG00000157554	ENST00000417133	P11308
ENSG00000157554	ENST00000429727	A0A088AWP2
ENSG00000157554	ENST00000442448	P11308
ENSG00000157554	ENST00000453032	A0A0C4DG41

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Transcriptional misregulation in cancer	KEGG	ko05202
Transcriptional misregulation in cancer	KEGG	hsa05202

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
20478527	2010	An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression.	337
19339269	2009	Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer.	191
19933109	2009	Induced chromosomal proximity and gene fusions in prostate cancer.	155
18505969	2008	Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer.	130
18519826	2008	Molecular genetics of successful smoking cessation: convergent genome-wide association study results.	130
20651988	2010	Antibody-based detection of ERG rearrangement-positive prostate cancer.	126
23817021	2013	ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss.	120
20713528	2010	FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells.	111
22705054	2012	Genomic deletion of PTEN is associated with tumor progression and early PSA recurrence in ERG fusion-positive and fusion-negative prostate cancer.	104
22736790	2012	The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: a cohort study and meta-analysis.	102

Citation

Roopika Menon ; Martin Braun ; Sven Perner

ERG (v-ets erythroblastosis virus E26 oncogene like (avian))

Atlas Genet Cytogenet Oncol Haematol. 2010-11-01

Online version: http://atlasgeneticsoncology.org/gene/53/favicon/apple-touch-icon.png

Historical Card

2006-08-01 ERG (v-ets erythroblastosis virus E26 oncogene like (avian)) by Liat Rainis-Ganon,Shai Izraeli Affiliation

Head, Research section, Pediatric Hemato-Oncology, Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel 52621