ERG

Synonyms: ETS-related gene

by Jan Klos

Background

It is a nuclear protein from the ETS family of transcription factors involved in regulation of embryonic development, cell proliferation, differentiation, angiogenesis, inflammation and apoptosis. It is encoded by ERG gene (Erythroblast transformation-specific [ETS]-related gene) localized on chr. 21q22.2. It is classified as proto-oncogene since its translocations and overexpression contribute to the development of malignant phenotype. Fusion with TMPRSS2 gene found in approximately half of all prostate cancers contributes to development of androgen-independence and is an indicator of worse prognosis. Fusion with EWS1 gene is found in 10% of Ewing sarcomas and fusion with TLS/FUS gene is found in acute myeloid leukemia with t(16;21) translocation.

Staining pattern

Staining pattern is nuclear.

Staining in normal cells

Nuclei of endothelial cells in blood and lymphatic vessels as well as bone marrow cells (early myelocytes).

Staining in tumors

ERG is expressed in virtually all benign and malignant endothelial neoplasms including hemangioendothelioma, angiosarcoma and Kaposi sarcoma. ERG is overexpressed due to gene rearrangement in cases of prostate adenocarcinoma (40-50% in Caucasians and <30% in Japanese and Koreans). This type of carcinoma expresses ERG due to a unique TMPRSS2-ERG gene fusion.  About 20% of small cell carcinoma of the prostate and 20-30% of high grade PIN are also positive. Among other than prostate carcinomas only few percent of high grade pancreatic intraepithelial neoplasia and few cases of urothelial carcinoma are reported positive.
Immunoreactivity is reported also in cases of: meningioma (80%), acute myeloid leukemia with t(16;21) and myeloid sarcoma (70%), synovial sarcoma (50%*), gastrointestinal stromal tumors (40%*), epithelioid sarcoma (40%), malignant rhabdoid tumor, Burkitt lymphoma and 10% Ewing sarcoma / PNET (due to EWSR1-ERG rearrangement). Few cases of desmoplastic small round cell tumor (DSRCT), epithelioid sarcoma, glomus tumor, synovial sarcoma, myoepithelioma, chondrosarcoma*, osteosarcoma*, rhabdomyosarcoma*, Wilm`s tumor and chordoma are also reported positive. Weak staining is reported in cases of blastic plasmacytoid dendritic cell neoplasm (BPDCN).
* Mostly detected with the Rabbit monoclonal antibody clone EPR3864 directed against the C-terminus of ERG.

Control tissue

Appendix

Application

  • Most sensitive marker of endothelial differentiation (only nuclear staining counts!) in tumors.
  • Immunohistochemical staining is a good surrogate marker for ERG gene fusion in the diagnosis of prostate cancer.
  • Some papers support that ERG positivity indicates worse prognostic subset of prostate adenocarcinoma (so far TMPRSS2-ERG gene fusion is described in prostate adenocarcinoma with only few exceptions) but conflicting results are reported.
  • In non-endothelial mesenchymal tumors the staining ERG is positive when using antibody against the C-terminus.

Selected references

  1. Lotan TL, Gupta NS, Wang W, et al. ERG gene rearrangements are common in prostatic small cell carcinomas. Mod Pathol. 2011 Jun;24(6):820-8. doi: 10.1038/modpathol.2011.7. Epub 2011 Feb 18.
  2. Miettinen M,Wang ZF, Paetau A, et al. ERG transcription factor as an immunohistochemical marker for vascular endothelial tumors and prostatic carcinoma. Am J Surg Pathol. 2011 Mar;35(3):432-41. doi: 10.1097/PAS.0b013e318206b67b.
  3. Miettinen M. Immunohistochemistry of soft tissue tumours review with emphasis on 10 markers. Histopathology. 2014 Jan;64(1):101-18. doi: 10.1111/his.12298. Epub 2013 Nov 28.
  4. He H, Magi-Galluzzi C, Li J, et al. The diagnostic utility of novel immunohistochemical marker ERG in the workup of prostate biopsies with “atypical glands suspicious for cancer”.  Am J Surg Pathol. 2011 Apr;35(4):608-14. doi: 10.1097/PAS.0b013e31820bcd2d. 
  5. BinXuMD, PhDa1MyriamChevarie-DavisMD, MSca1SimoneChevalierPhDb et al. The prognostic role of ERG immunopositivity in prostatic acinar adenocarcinoma: a study including 454 cases and review of the literature. Hum Pathol 2014 Mar;45(3):488-97.  doi: 10.1016/j.humpath.2013.10.012. Epub 2013 Oct 23.