ETV6

Primary Author(s)*

Brian Davis PhD

Synonyms

"E26 transformation-specific variant 6"; "E-twenty-six variant 6"; ETS Variant 6; "Translocation-ETS-Leukemia"; TEL; THC5; TEL/ABL

Genomic Location

Cytoband: 12p13.2

Genomic Coordinates:

chr12:11,802,788-12,048,336(GRCh37/hg19)

chr12:11,649,854-11,895,402(GRCh38/hg38)

Cancer Category/Type

This ETV6 gene, either as a translocation partner with dozens of partner genes or as simple substitution mutations is found at a low level in many cancers see COSMIC), but is more prominent as a fusion protein in a number of hematological malignancies [1,2,see OMIM].

The t(12;21)(p13;q22) resulting in ETV6-RUNX1 fusion has been found in 25% of childhood B-cell acute lymphoblastic leukemia (B-ALL), but are much less common in adult B-ALL (only 2%) [2]. The fusion protein produced by the translocation confers a dominant negative effect on the normal RUNX1 protein, resulting in transcriptional activation become transcriptional repression (1,2]. The t(12;21) confers a favorable prognosis with cures seen in >90% of childhood B-ALL [1].

ETV6 fused with PDGFRB has been found in patients with 'chronic myelomonocytic leukemia (Golub et al. (1994) and chronic myeloproliferative disorder Apperley et al. (2002). acute lymphocytic leukemia ETV6/RUNX1 Golub et al. (1995). The ETV6-PDGFRA fusion gene has been found in patients with chronic eosinophilic leukaemia (CEL), and these patients responded to low-dose imatinib [1].

Gene Overview

The ETV6 gene encodes one of 29 proteins in the ETS family of transcription factors ("ETS" is from "E26 transformation-specific" or "E-twenty-six"). The Etvs6 protein contains two functional domains: a N-terminal pointed (PNT) that is involved in protein-protein interactions with itself and other proteins, and a C-terminal, helix-loop-helix, DNA-binding domain (the ETS domain). Normally, the Etv6 protein acts as a transcriptional repressor and tumor supressor [2]. Familial genetic studies have shown that the protein is required for hematopoiesis and hematologic and other malignancies [3,4]. This gene is known to be involved in a large number of chromosomal rearrangements (over 30 fusion partners) associated with leukemia and congenital fibrosarcoma (adapted from NCBI Gene description). In most translocations, the N-terminal PNT domain of ETV6 is fused to a partner gene and acts as an aggregator for other proteins for a variety of effects, including transcriptional repression (eg, EVT6-RUNX1) [1,2] and constitutively activated tyrosine kinases (eg, ETV6-PDGFRB) [1].

Common Alteration Types

ETV6 has been identified as a fusion partner in at least 30 chromosomal translocation genes [3, Atlas of Genetics and Cytogenetics in Oncology and Haematology, OMIM]. In most translocations, the N-terminal PNT domain of ETV6 is fused to a partner gene and acts as an aggregator for other proteins for a variety of effects, including transcriptional repression (eg, EVT6-RUNX1) [1, 2] and constitutive activated tyrosine kinases (eg, ETV6-PDGFRB) [1]. A large number of simple substitution mutations have been found spread throughout the gene and these have been found in a large number of human malignancies at relatively low percentages (see COSMIC and see Cancer Index).

ETV6/PDGFRB fusion

ETV6/MN1 fusion

ETV6/AML1 fusion

ETV6/ARNT fusion

ETV6/MDS2 fusion

ETV6/ABL2 fusion

ETV6/PER1 fusion

ETV6/NTRK3 fusion

ETV6/ACS2 fusion

ETV6/BTL fusion

ETV6/JAK2 fusion

ETV6/RUNX1 fusion

Copy Number Loss	Copy Number Gain	LOH	Loss-of-Function Mutation	Gain-of-Function Mutation	Translocation/Fusion
	X	X	X	X	X

External Links

ETV6 by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information

ETV6 by COSMIC - sequence information, expression, catalogue of mutations

ETV6 by St. Jude ProteinPaint mutational landscape and matched expression data.

ETV6 by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs

ETV6 by Cancer Index - gene, pathway, publication information matched to cancer type

ETV6 by OncoKB - mutational landscape, mutation effect, variant classification

ETV6 by My Cancer Genome - brief gene overview

ETV6 by UniProt - protein and molecular structure and function

ETV6 by Pfam - gene and protein structure and function information

ETV6 by GeneCards - general gene information and summaries

ETV6 by NCBI Gene - general gene information and summaries

ETV6 by OMIM - compendium of human genes and genetic phenotypes

ETV6 by LOVD(3) - Leiden Open Variation Database

ETV6 by TICdb - database of Translocation breakpoints In Cancer

References

1 .Arber DA, et al., (2008). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p117-118.

2. Schafer, E.S. . et al. (2015). Molecular Genetics of Acute Lymphoblastic Leukemia in The Molecular Basis of Cancer, 4th edition. Mendelsohn, J, Howley, PM, Israel, MA, Gray, JW, Thompson, CB. Editors. Elsevier Press: Philadelphia, USA, p395-406.

3. Hock, H. et al. (2017). ETV6 in Hematopoiesis and Leukemia Predisposition. Semin Hematol. 54: 98-104. PMID 28637624 DOI: 10.1053/j.seminhematol.2017.04.005

4. Zhang, M.Y et al. (2015). Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy, Nature Genet. 47: 180–185. PMID 25581430 DOI: 10.1038/ng.3177

Notes

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