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Other entities represented in this entry:
HGNC Approved Gene Symbol: ERG
Cytogenetic location: 21q22.2 Genomic coordinates (GRCh38): 21:38,367,261-38,661,783 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 21q22.2 | Lymphatic malformation 14 | 620602 | Autosomal dominant | 3 |
Reddy et al. (1987) isolated a cDNA representing the complete coding sequence of oncogene ERG. Two regions of the predicted 363-residue protein share about 40% and 70% homology with the 5-prime and 3-prime regions of the viral Ets oncogene (see ETS1; 164720), respectively, suggesting that ERG belongs to the ETS oncogene family.
By sequence analysis, Rao et al. (1987) identified 2 different ERG transcripts, ERG1 and ERG2. ERG2 differs from ERG1 by a splicing event that causes a frameshift resulting in an additional 99 amino acids at the N terminus. In vitro transcription and translation resulted in 2 polypeptides of approximately 41 and 52 kD. Rao et al. (1987) concluded that alternative sites of splicing and polyadenylation, together with alternative sites of translation initiation, allow synthesis of 2 ERG polypeptides.
Owczarek et al. (2004) stated that 5 alternatively spliced ERG transcripts encode 5 proteins of 38 to 55 kD, all of which bind DNA at ETS sites and act as transcriptional activators. By database analysis and RT-PCR, they identified 4 additional ERG transcripts. RT-PCR analysis of 6 ERG variants showed variable expression in placenta and most human cell lines examined.
Using RT-qPCR and immunoblotting, Greene et al. (2023) observed that total cellular expression of ERG was the same in primary human dermal lymphatic endothelial cells (HDLECs) and in human umbilical vein endothelial cells. Immunofluorescence microscopy of cultured HDLECs showed that ERG expression colocalized with the lymphatic endothelial cell nuclear marker PROX1 (601546), a finding that was confirmed in vivo by immunostaining whole mounts of ear skin from 3-week-old mice. Overexpression of wildtype ERG in HEK293 cells recapitulated the nuclear expression pattern observed in the HDLEC and mouse ear skin models.
Murakami et al. (1993) found that ERG2 is a nuclear phosphoprotein that binds purine-rich sequences. With a half-life of 21 hours, it is considerably more stable than the short-lived ETS1 and ETS2 (164740) proteins. Like other ETS proteins, ERG2 is a sequence-specific DNA-binding protein and is expressed at higher levels in early myeloid cells than in mature lymphoid cells. Murakami et al. (1993) suggested that ERG2 acts as a regulator of genes required for maintenance and/or differentiation of early hematopoietic cells.
Using binding studies and reporter gene assays, Oram et al. (2010) found that ERG and FLI1 (193067) bound and activated the intermediate promoter of the LMO2 gene (180385) in T-cell acute lymphoblastic leukemia (T-ALL) samples. LMO2 also bound enhancers in the FLI1 and ERG loci, and all 3 proteins bound an enhancer element in the first intron of the hematopoietically expressed HHEX gene (604420) and upregulated expression of an HHEX reporter gene. Oram et al. (2010) proposed that a self-sustaining triad of LMO2, ERG, and FLI1 are involved in T-ALL by stabilizing HHEX expression.
Bose et al. (2017) showed that ERF (611888) mutations in prostate cancer cause decreased protein stability and mostly occur in tumors without ERG upregulation. ERF loss recapitulated the morphologic and phenotypic features of ERG gain in normal mouse prostate cells, including expansion of the androgen receptor (AR; 313700) transcriptional repertoire, and ERF had tumor suppressor activity in the same genetic background of PTEN (601728) loss that yields oncogenic activity by ERG. In the more common scenario of ERG upregulation, chromatin immunoprecipitation followed by sequencing indicated that ERG inhibits the ability of ERF to bind DNA at consensus ETS sites both in normal and in cancerous prostate cells. Consistent with a competition model, ERF overexpression blocked ERG-dependent tumor growth, and ERF loss rescued TMPRSS2-ERG-positive prostate cancer cells from ERG dependency. Bose et al. (2017) concluded that their data provided evidence that the oncogenicity of ERG is mediated, in part, by competition with ERF, and raised the larger question of whether other gain-of-function oncogenic transcription factors might also inactivate endogenous tumor suppressors.
Owczarek et al. (2004) determined that the ERG gene contains at least 17 exons and spans 282 kb. The 5-prime end contains a major CpG island. A region upstream of exon 1 and a 1-kb region within intron 1 contain multiple transcription factor-binding sites. Owczarek et al. (2004) noted that not all exons of human ERG are conserved in mouse Erg.
By somatic cell hybrid analysis, Rao et al. (1987) mapped the ERG oncogene to chromosome 21. By family linkage studies to DNA markers translocated along with ETS2 to the derivative chromosome 8 in the t(8;21) translocation of acute myelogenous leukemia (AML; 601626), Sacchi et al. (1988) concluded that the ETS2 gene is located about 17 cM from the breakpoint. By family linkage studies using RFLPs, Sacchi et al. (1988) demonstrated that ERG is situated just proximal to ETS2. Rao et al. (1988) and Modi et al. (1989) concluded from in situ hybridization and somatic cell hybridization that the ERG gene is located at chromosome 21q22.3.
Owczarek et al. (2004) mapped the mouse Erg gene to a region of chromosome 16 that shares incomplete homology of synteny with human chromosome 21q22.2-q22.3.
Rao et al. (1988) found that the ERG gene is translocated from chromosome 21 to chromosome 8 in the t(8;21)(q22;q22), a nonrandom translocation found in patients with acute myelogenous leukemia of the subtype M2 (AML-M2).
ERG/FUS and ERG/EWS Fusion Genes
Ichikawa et al. (1994) demonstrated that in human myeloid leukemia with the t(16;21)(p11;q22) translocation the ERG gene is fused with the TLS/FUS gene (137070) on chromosome 16. The chimeric gene product is an RNA-binding protein that is highly homologous to the product of the EWS gene (133450) involved in Ewing sarcoma (ES; 612219). Thus, the FUS/ERG gene fusion in t(16;21) leukemia was predicted to produce a protein similar to the EWS/ERG chimeric protein seen in Ewing sarcoma.
Ewing sarcoma, the second most common malignant bone tumor of children and young adults, is an aggressive osteolytic tumor with a marked propensity for dissemination. It belongs to the heterogeneous group of small round cell tumors that are often a diagnostic challenge to the pathologist and clinical oncologist. Ewing sarcoma and related peripheral primitive neuroectodermal tumors (PNETs or 'peanut' tumors) show a t(11;22) translocation or a (21,22) rearrangement that is associated with hybrid transcripts of the EWS gene with the FLI1 (193067) or ERG gene. ERG is a member of the ETS family of transcription factors closely related to FLI1. The chimeric protein resulting from the fusion of EWS with ERG is structurally similar to the typical EWS-FLI1 protein in which the N-terminal portion of EWS is linked to the ETS domain of ERG. Delattre et al. (1994) explored the possibility that these fusion genes may be the defining criterion for the Ewing family of tumors. Samples of RNA from 114 tumors were reverse transcribed and subjected to the polymerase chain reaction with primers designed to amplify the relevant chimeric transcripts. In-frame transcripts were observed in 89 cases. A hybrid transcript was found in 83 of 87 cases (95%) of Ewing sarcoma or peripheral primitive neuroectodermal tumors. Altogether, 78 tumors contained an EWS-FLI1 fusion transcript and 11 tumors had an EWS-ERG fusion transcript. Four different EWS-ERG junctions were found. Kretschmar (1994) discussed the diagnostic and therapeutic potential of these findings. The abnormal fusion transcript might, for example, be targeted and scrambled by specific antisense oligonucleotides, leading to improved eradication of disease in children with these neoplasms based on biology-specific therapy.
By Western blot analysis, Yang et al. (2000) showed that the N-terminal domain of TLS binds to RNA polymerase II and that this binding is retained by the TLS-ERG fusion protein. However, the C-terminal domain of TLS is required for interaction with the serine-arginine (SR) splicing factor SC35 (SFRS2; 600813) and the TLS-associated SR proteins TASR1 and TASR2; this binding is lost in the TLS-ERG fusion protein because ERG replaces the C terminus of TLS.
ERG/TMPRSS2 Fusion Gene
Tomlins et al. (2005) used a bioinformatics approach to discover candidate oncogenic chromosomal aberrations on the basis of outlier gene expression. Two ETS transcription factors, ERG and ETV1 (600541), were identified as outliers in prostate cancer (see 176807). Tomlins et al. (2005) identified recurrent gene fusions of the 5-prime untranslated region of TMPRSS2 (602060) to ERG or ETV1 in prostate cancer tissues with outlier expression. Using FISH, Tomlins et al. (2005) demonstrated that 23 of 29 prostate cancer samples harbored rearrangements in ERG or ETV1. Cell line experiments suggested that the androgen-responsive promoter elements of TMPRSS2 mediate the overexpression of ETS family members in prostate cancer.
The TMPRS22 and ERG genes are arranged tandemly on chromosome 21q22. The TMPRSS2/ERG fusion joins TMPRSS2 exons 1 or 2 usually to ERG exons 2, 3 or 4, which results in activation of the ERG transcription factor. This fusion separates the ERG 3-prime centromeric regions from the 5-prime telomeric ends; deletions of this region can also occur. Attard et al. (2008) performed FISH studies of the TMPRS22/ERG genes in 445 prostate cancers from patients who had been managed conservatively. They identified an alteration, called 2+Edel, characterized by duplication of the TMPRS22/ERG fusion (detected as duplication of 3-prime ERG sequence) together with interstitial deletion of 5-prime ERG sequences. The alteration was found in 6.6% of cancers and was associated with very poor clinical outcome compared to cancers with normal ERG loci (25% vs 90% survival at 8 years). Cancers with 1 copy of 3-prime ERG (1Edel) did not have a worse clinical outcome. The findings were consistent with the hypothesis that overexpression of ERG that results from the fusion of 5-prime TMPRSS2 to 3-prime ERG is responsible for driving cancer progression. Attard et al. (2008) suggested that determination of ERG gene status, including duplication of the fusion of TMPRSS2 to ERG sequences in 2+Edel, may allow stratification of prostate cancer into distinct survival categories.
Using dual-color FISH in LNCaP prostate cancer cells, which are androgen-sensitive but lack the TMPRSS2-ERG fusion gene, Mani et al. (2009) observed that stimulation with the androgen receptor (AR; 313700) ligand dihydrotestosterone (DHT) for 60 minutes induced proximity between the TMPRSS2 and ERG genomic loci. The effect was dependent upon AR, as the same proximity was not induced in an androgen-insensitive prostate cancer cell line. To determine whether the induced proximity facilitates formation of these gene fusions, Mani et al. (2009) treated LNCaP cells with DHT for 12 hours and then irradiated the cells to induce DNA double-strand breaks. TMPRSS2-ERG fusions were detected in 25% of clones treated with 3-Gy irradiation but in only 2.3% of those treated with 1-Gy. Mani et al. (2009) speculated that androgen signaling colocalizes the 5- and 3-prime gene fusion partners, thereby increasing the probability of a gene fusion when subjected to agents that cause DNA double-strand breaks.
Using a Bayesian statistical method (BeviMed) to obtain a posterior probability of association between variation in 19,663 protein-coding genes and a case set of 94 probands with primary lymphedema (LMPHM14; 620602), Greene et al. (2023) identified a dominant genetic association between primary lymphedema and frameshift variants in the ERG gene (see, e.g., 165080.0001-165080.0003) in 4 affected individuals from 3 unrelated families. A participant in a fourth family, enrolled in 100KGP for an unrelated condition, also carried a predicted ERG loss-of-function variant and was found to have additional features consistent with primary lymphedema. Functional analysis demonstrated mislocalization of the mutant ERG in the cytosol rather than the nucleus, which would prevent it from binding to DNA and exerting its function as a transcription factor. The authors suggested that defective lymphangiogenesis in these ERG-associated primary lymphedema cases might result from reduced ERG availability in the nucleus, due to haploinsufficiency from nonsense-mediated decay or due to mislocalization.
In a sister and brother with primary lymphedema (LMPHM14; 620602), Greene et al. (2023) identified heterozygosity for a frameshift mutation in the ERG gene that was predicted to extend the protein (Asn463ThrfsTer42). The mutation status of their affected father, or of their unaffected mother and brother, was not reported.
In a male patient with primary lymphedema (LMPHM14; 620602), Greene et al. (2023) identified heterozygosity for a frameshift mutation in the ERG gene that was predicted to result in a premature termination codon (Thr224ArgfsTer15). His unaffected parents did not carry the mutation, indicating that the variant arose de novo in the proband. Overexpression of mutant cDNA in HEK293 cells resulted in mislocalization of ERG outside of the nucleus, in the cytosol, which would prevent it from binding to DNA and exerting its function as a transcription factor. The authors suggested that defective lymphangiogenesis in the proband might result from reduced ERG availability in the nucleus, due to haploinsufficiency from nonsense-mediated decay or due to mislocalization.
In a female patient with primary lymphedema (LMPHM14; 620602), Greene et al. (2023) identified heterozygosity for a frameshift mutation in the ERG gene that was predicted to result in a premature termination codon (Ser182AlafsTer22). Her affected father was initially called homozygous for the reference allele, suggesting a lack of cosegregation of the variant with the disease in that pedigree. However, a review of the genome sequencing read alignments for the father revealed that he was mosaic for the 1-bp deletion of a single G within the central poly-G tract of the motif AGCTGGGGGTGAG. The authors noted that this was consistent with the observation that his lymphedema became clinically apparent more than 2 decades later than that of his daughter, indicating milder disease. Overexpression of mutant cDNA in HEK293 cells resulted in mislocalization of ERG outside of the nucleus, in the cytosol, which would prevent it from binding to DNA and exerting its function as a transcription factor. The authors suggested that defective lymphangiogenesis in the proband and her father might result from reduced ERG availability in the nucleus, due to haploinsufficiency from nonsense-mediated decay or due to mislocalization.
Attard, G., Clark, J., Ambroisine, L., Fisher, G., Kovacs, G., Flohr, P., Berney, D., Foster, C. S., Fletcher, A., Gerald, W., Moller, H., Reuter, V., De Bono, J. S., Scardino, P., Cuzick, J., Cooper, C. S. Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene 27: 253-263, 2008. [PubMed: 17637754] [Full Text: https://doi.org/10.1038/sj.onc.1210640]
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Delattre, O., Zucman, J., Melot, T., Garau, X. S., Zucker, J.-M., Lenoir, G. M., Ambros, P. F., Sheer, D., Turc-Carel, C., Triche, T. J., Aurias, A., Thomas, G. The Ewing family of tumors--a subgroup of small-round-cell tumors defined by specific chimeric transcripts. New Eng. J. Med. 331: 294-299, 1994. [PubMed: 8022439] [Full Text: https://doi.org/10.1056/NEJM199408043310503]
Greene, D., Genomics England Research Consortium, Pirri, D., Frudd, K., Sackey, E., Al-Owain, M., Giese, A. P. J., Ramzan, K., Riaz, S., Yamanaka, I., Boeckx, N., Thys, C., and 22 others. Genetic association analysis of 77,539 genomes reveals rare disease etiologies. Nature Med. 29: 679-688, 2023. [PubMed: 36928819] [Full Text: https://doi.org/10.1038/s41591-023-02211-z]
Ichikawa, H., Shimizu, K., Hayashi, Y., Ohki, M. An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocation . Cancer Res. 54: 2865-2868, 1994. [PubMed: 8187069]
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Murakami, K., Mavrothalassitis, G., Bhat, N. K., Fisher, R. J., Papas, T. S. Human ERG-2 protein is a phosphorylated DNA-binding protein--a distinct member of the ETS family. Oncogene 8: 1559-1566, 1993. [PubMed: 8502479]
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Rao, V. N., Modi, W. S., Drabkin, H. D., Patterson, D., O'Brien, S. J., Papas, T. S., Reddy, E. S. The human ERG gene maps to chromosome 21, band q22: relationship to the 8;21 translocation of acute myelogenous leukemia. Oncogene 3: 497-500, 1988. [PubMed: 3274086]
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Reddy, E. S. P., Rao, V. N., Papas, T. S. The ERG gene: a human gene related to the ETS oncogene. Proc. Nat. Acad. Sci. 84: 6131-6135, 1987. [PubMed: 3476934] [Full Text: https://doi.org/10.1073/pnas.84.17.6131]
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Tomlins, S. A., Rhodes, D. R., Perner, S., Dhanasekaran, S. M., Mehra, R., Sun, X.-W., Varambally, S., Cao, X., Tchinda, J., Kuefer, R., Lee, C., Montie, J. E., Shah, R. B., Pienta, K. J., Rubin, M. A., Chinnaiyan, A. M. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310: 644-648, 2005. [PubMed: 16254181] [Full Text: https://doi.org/10.1126/science.1117679]
Yang, L., Embree, L. J., Hickstein, D. D. TLS-ERG leukemia fusion protein inhibits RNA splicing mediated by serine-arginine proteins. Molec. Cell. Biol. 20: 3345-3354, 2000. [PubMed: 10779324] [Full Text: https://doi.org/10.1128/MCB.20.10.3345-3354.2000]