ETV6-NTRK3 gene fusion is the translocation of genetic material between the ''

ETV6 ETV6 (i.e. translocation-Ets-leukemia virus) protein is a transcription factor that in humans is encoded by the ''ETV6'' (previously known as ''TEL'') gene. The ETV6 protein regulates the development and growth of diverse cell types, particularly ...

'' gene located on the short arm (designated p) of chromosome 12 at position p13.2 (i.e. 12p13.2) and the ''

NTRK3 Tropomyosin receptor kinase C (TrkC), also known as NT-3 growth factor receptor, neurotrophic tyrosine kinase receptor type 3, or TrkC tyrosine kinase is a protein that in humans is encoded by the ''NTRK3'' gene. TrkC is the high affinity catalyt ...

'' gene located on the long arm (designated q) of chromosome 15 at position q25.3 (i.e. 15q25.3) to create the (12;15)(p13;q25) fusion gene, ''ETV6-NTRK3''. This new gene consists of the

5' end Directionality, in molecular biology and biochemistry, is the end-to-end chemical orientation of a single strand of nucleic acid. In a single strand of DNA or RNA, the chemical convention of naming carbon atoms in the nucleotide pentose-sugar-ri ...

of ''ETV6'' fused to the

3' end Directionality, in molecular biology and biochemistry, is the end-to-end chemical orientation of a single strand of nucleic acid. In a single strand of DNA or RNA, the chemical convention of naming carbon atoms in the nucleotide pentose-sugar-ri ...

of ''NTRK3''. ''ETV6-NTRK3'' therefore codes for a chimeric

oncoprotein An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

consisting of the helix-loop-helix (HLH) protein dimerization domain of the ETV6 protein fused to the

tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...

(i.e. PTK) domain of the NTRK3 protein. The ''ETV6'' gene codes for the

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

protein, ETV6, which suppresses the expression of, and thereby regulates, various genes that in mice are required for normal

hematopoiesis Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. ...

as well as the development and maintenance of the vascular network. ''NTRK3'' codes for

Tropomyosin receptor kinase C Tropomyosin receptor kinase C (TrkC), also known as NT-3 growth factor receptor, neurotrophic tyrosine kinase receptor type 3, or TrkC tyrosine kinase is a protein that in humans is encoded by the ''NTRK3'' gene. TrkC is the high affinity catalyt ...

a NT-3 growth factor receptor cell surface protein that when bound to its growth factor ligand,

neurotrophin-3 Neurotrophin-3 is a protein that in humans is encoded by the ''NTF3'' gene. The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a protein growth factor which has activi ...

, becomes an active tyrosine kinase that phosphorylates tyrosine residues on, and thereby stimulates,

signaling proteins In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...

that promote the growth, survival, and proliferation of their parent cells. The

of the ETV6-NTRK3 fusion protein is dysfunctional in that it is continuously active in phosphorylating

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...

residues on, and thereby continuously stimulating, proteins that promote the growth, survival, and proliferation of their parent cells. In consequence, these cells take on malignant characteristics and are on the pathway of becoming cancerous. Indeed, the ''ETV6-NTRK3'' fusion gene appears to be a critical driver of several types of cancers. It was originally identified in congenital

fibrosarcoma Fibrosarcoma (fibroblastic sarcoma) is a malignant mesenchymal tumour derived from fibrous connective tissue and characterized by the presence of immature proliferating fibroblasts or undifferentiated anaplastic spindle cells in a storiform patte ...

and subsequently found in

mammary secretory carcinoma Mammary secretory carcinoma (MSC), also termed secretory carcinoma of the breast, is a rare form of the breast cancers. MSC usually affects women but in a significant percentage of cases also occurs in men and children. Indeed, McDvitt and Stewart ...

(also termed juvenile breast cancer),

mammary analogue secretory carcinoma Mammary analogue secretory carcinoma (MASC), also termed MASCSG, (the "SG" subscript indicates salivary gland) is a salivary gland neoplasm. It is a secretory carcinoma which shares the microscopic pathologic features with other types of secretory ...

of salivary glands (also termed MASC or MASC_SG), salivary gland–type carcinoma of the thyroid, secretory carcinoma of the skin, congenital fibrosarcoma, congenital

mesoblastic nephroma Congenital mesoblastic nephroma, while rare, is the most common kidney neoplasm diagnosed in the first three months of life and accounts for 3-5% of all childhood renal neoplasms. This neoplasm is generally non-aggressive and amenable to surgical r ...

, rare cases of

acute myelogenous leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may include ...

, ALK-negative

Inflammatory myofibroblastic tumour Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm of the mesodermal cells that form the connective tissues which support virtually all of the organs and tissues of the body. IMT was formerly termed inflammatory pseudotumor. Currently, ...

cholangiocarcinoma Cholangiocarcinoma, also known as bile duct cancer, is a type of cancer that forms in the bile ducts. Symptoms of cholangiocarcinoma may include abdominal pain, yellowish skin, weight loss, generalized itching, and fever. Light colored stool ...

, and radiation-induced

papillary thyroid carcinoma Papillary thyroid cancer or papillary thyroid carcinoma is the most common type of thyroid cancer, representing 75 percent to 85 percent of all thyroid cancer cases.Chapter 20 in: 8th edition. It occurs more frequently in women and presents in th ...

NTRK3 inhibitors in clinical development

Because cancers associated with the expression of the ETV6-NTRK3 fusion protein are known or suspected of being a direct consequence of overly active ETV6-NTRK3's tyrosine kinase, it has been proposed that

tyrosine kinase inhibitor A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosph ...

s with specificity for NTRK3 may be of therapeutic usefulness in these cancers.

Entrectinib Entrectinib, sold under the brand name Rozlytrek, is an anti-cancer medication used to treat ROS1-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. It is a selective tyrosine kinase inhibitor (TKI), of the tropomyosin r ...

is a pan-NTRK as well as an ALK and ROS1 tyrosine kinase inhibitor has been found useful in treating a single patient with ''ETV6-NRTK3'' fusion gene-associated

and has lend support to the clinical development of NTRK3-directed tyrosine kinase inhibitors to treat ETV6-NTRK3 fusion protein associated malignancies. Three clinical trials are in the recruitment phase for determining the efficacy of treating a wide range of solid tumors associated with mutated overactive tyrosine kinase proteins, including the ETV6-TRK3 protein, with

larotrectinib Larotrectinib, sold under the brand name Vitrakvi, is a medication for the treatment of cancer. It is an inhibitor of tropomyosin kinase receptors TrkA, TrkB, and TrkC. It was discovered by Array BioPharma and licensed to Loxo Oncology in 201 ...

, a non-selective inhibitor of NTRK1, NTRK2, and NTRK3 tyrosine kinases. Larotrectinib was approved by the FDA on November 26, 2018.

References

{{DEFAULTSORT:Etv6-Ntrk3 Gene Fusion Oncogenes