RET
In databases:
● Ensembl (http://www.ensembl.org/index.html): ENSG00000165731
● GeneCards (http://www.genecards.org/): RET
● HGNC (http://www.genenames.org/): 9967 or RET
● Enzyme Number (IUBMB): EC 2.7.10.-, EC 2.7.10.1
Gene locus:
10q11.2
Protein name:
Ret proto-oncogene
Protein Size:
1114 amino acids; about 124 kDa
Function :
The protein encoded by RET is a a tyrosine kinase receptor whose ligands are neurotrophic factors of the glial-cell line derived neurotrophic factor (GDNF) family, including GDNF, neurturin, artemin and persefin. RET plays a crucial role in neural crest development, and it can undergo oncogenic activation in vivo and in vitro by cytogenetic rearrangement.
Cancer-related alterations:
Germline RET mutations cause autosomal dominant inherited multiple endocrine neoplasia type 2 (MEN2A and MEN2B) and familial medullary thyroid carcinoma only (FMTC).
MEN2A is the most frequent form of medullary thyroid cancer (MTC). It is an inherited cancer syndrome characterized by MTC, pheochromocytoma (50% of cases) and/or hyperparathyroidism (5 to 20% of cases).
MEN2B is an uncommon inherited cancer syndrome characterized by predisposition to MTC and pheochromocytoma which is associated with marfanoid habitus, mucosal neuromas, skeletal and ophtalmic abnormalities, and ganglioneuromas of the intestine tract. Then the disease progresses rapidly with the development of metastatic MTC and a pheochromocytome in 50% of cases.
In FMTC, which occurs in 25-30% of MTC cases, MTC is the only clinical manifestation.
All mutations are “missense” activating mutations. There are widely dispersed in 7/21 exons of RET with phenotype-genotype relationships: mutations in exon 11 are strongly associated with MEN2A phenotype, mutations in exon 16 or exons 8, 10, 13, 14, 15, with MEN2B and FMTC (rarely MEN2A) phenotypes respectively.
Germline RET mutations are also associated to the autosomal inherited Hirschprung's disease or colonic aganglionosis (HSCR) which represents 15-20% of HSCR cases. HSCR (1/5000 live births) is a genetic disorder of neural crest development characterized by the absence of intramural ganglion cells in the hindgut, often resulting in intestinal obstruction. Occasionally, MEN2A or FMTC occur in association with HSCR. RET mutations are loss-of-function mutations dispersed throughout the RET coding sequence and include deletions, insertions, frameshift missense and nonsense mutations.
Somatic RET mutations have been identified in sporadic medullary thyroid carcinoma (MTC), papillary thyroid carcinoma (PTC) and pheochromocytoma.
MTC is a common tumor derived from the C cells of the thyroid that typically arises as an irregular, solid or cystic mass from otherwise normal thyroid tissue.
PTC is a malignant neoplasm characterized by the formation of numerous, irregular, finger-like projections of fibrous stroma that is covered with a surface layer of neoplastic epithelial cells.
Pheochromocytoma is a catecholamine-producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent.
Chromosomal aberrations involving RET are found in PTC. Several activating genes rearrange with the RET genomic region coding for the tyrosine kinase domain. Inversion inv(10)(q11.2;q21) generates the RET-CCDC6 oncogene;
inversion inv(10)(q11.2;q11.2) generates the RET-NCOA4 oncogene;
translocation t(10;14)(q11;q32) with GOLGA5 generates the RET/GOLGA5 oncogene;
translocation t(8;10)(p21.3;q11.2) with PCM1 generates the PCM1/RET oncogene;
translocation t(6;10)(p21.3;q11.2) with TRIM27 generates the TRIM27-RET oncogene;
translocation t(1;10)(p13;q11) with TRIM33 generates the TRIM33-RET oncogene;
translocation t(7;10)(q32;q11) with TRIM24 generates the TRIM24-RET oncogene.
translocation t(1;10)(q21;q11) with NTRK1 generates the NTRK1-RET oncogene ;
translocation t(10;12)(q11;p13) with ERC1 generates the ERC1-RET oncogene;
translocation t(10;14)(q11.2;q22.1) with KTN1 generates the KTN1-RET oncogene ;
translocation t(10;17)(q11;q24) with PRKAR1A generates the PRKAR1A-RET oncogene.
Somatic mutations have been observed in thyroid (about one-third of cases), adrenal gland, urinary tract, large intestine (colorectal cancer) and ovarian tumors. A mutational hot spot corresponds to amino acid 918. Substitution “missenses” are the most frequent mutations.
Therapy:
In PTC, chromosomal rearrangements are the primary oncogenic event and are difficult to treat. Conventional therapy for progressive metastatic MTC is limited. Small-molecule tyrosine kinase inhibitors can target multiple kinases at nanomolar concentrations, including RET, and have shown efficacy against a variety of malignancies. Initial clinical evidence suggests that several of these inhibitors, including sorafenib, vandetanib, motesanib, sunitinib, and XL-184, may have some benefit in treating progressive MTC. Although initial success seen in these trials seems to be modest, it represents a major breakthrough in the treatment of patients with widespread metastatic MTC.
References (open access):
How to Treat a Signal? Current Basis for RET-Genotype-Oriented Choice of Kinase Inhibitors for the Treatment of Medullary Thyroid Cancer. Prazeres H, Torres J, Rodrigues F, Couto JP, Vinagre J, Sobrinho-Simões M, Soares P. J Thyroid Res. 2011;2011:678357.
The evolving field of tyrosine kinase inhibitors in the treatment of endocrine tumors. Ye L, Santarpia L, Gagel RF. Endocr Rev. 2010 Aug;31(4):578-99.
The many faces of RET dysfunction in kidney. Jain S. Organogenesis. 2009 Oct;5(4):177-90.
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