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RET (REarranged during Transfection)

Identity

HGNC (Hugo) RET
LocusID (NCBI) 5979
Location 10q11.21
Location_base_pair Starts at 43572517 and ends at 43622952 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Note proto-oncogene See also the Deep insight on RET point mutations in Thyroid Carcinoma.

DNA/RNA

Description 21 exons, 3415 pb
Transcription 3 mains alternative spliced mRNA in the 3' region

Protein

Description Several isoforms; 3 main isoforms detected in human :
  • long isoform (RET51): 1114 amino acids ;
  • middle isoform (RET 43): 1106 amino acids ;
  • short isoform (RET 9) : 1072 amino acids.
  • Expression RET is mainly expressed in tumors of neural crest origin : medullary thyroid carcinoma, pheochromocytoma, neuroblastoma.
    In human embryos, RET is expressed in a cranial population of neural crest cells, and in the developing nervous and urogenital systems.
    RET expression is found in several crest-derived cell lines, spleen, thymus, lymph nodes, salivary glands, spermatogonia, and recently in normal thyroid tissue, thyroid adenoma and both papillary and follicular thyroid cell neoplasias.
    Function RET is 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 activation is mediated via different glycosyl phosphatidylinositol-linked GRF_ receptors.
    Homology General structure is similar to other tyrosine kinase receptors but RET differs by the presence of a cadherin domain in its extracellular region.

    Mutations

    Germinal Germline RET mutations causes autosomal dominant inherited multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma only (FMTC). All these mutations are missense activating mutations. There are widely dispersed in 7/21 exons of RET with phenotype-genotype relationships : mutations in exon 11 is strongly associated with MEN2A phenotype, mutations in exon 16 or exons 8, 10, 13, 14, 15, with NEM2B and FMTC (rarely NEM2A) phenotypes respectively.
    Germline RET mutations are associated to the autosomal inherited Hirschprung's disease or colonic aganglionosis (HSCR) which represents 15-20% of HSCR cases. RET mutations are loss-of-function mutations dispersed throughout the RET coding sequence and include deletions, insertions, frameshift missense and nonsense mutations.
    Somatic Somatic RET mutations have been identified in sporadic medullary thyroid carcinoma (MTC) and pheochromocytoma, mostly located in exon 16 at codon 918 (30-70% of sporadic MTC). Somatic mutations in exons 15, codon 883 and in exon 13, codon 768 have been also detected in rare cases of sporadic MTC.
    Somatic rearranged forms of RET (RET/PTC) are detected in human papillary thyroid carcinoma (PTC) : several activating genes rearrange with RET to form RET/PTC by juxtaposing the genomic region coding for the tyrosine kinase domain with the 5'-terminal regions of several unrelated genes : H4: PTC1; RIa: PTC2 ; ELE1: PTC3/4 ; RFG5: PTCT5 ; hTIF1: PTC6 ; RFG7: PTC7, and ELKS.
    RET rearrangement as RET/PTC1 is mostly detected in typical sporadic papillary thyroid carcinoma, RET/PTC3 occured at high frequency in chilhood papillary thyroid carcinoma from areas contaminated by the Chernobyl nuclear reactor accident.

    Implicated in

    Entity Multiple Endocrine Neoplasia type 2 (MEN2), Hirschprung's disease (HSCR). Somatic rearranged forms of RET (RET/PTC) are detected in human papillary thyroid carcinoma.
    Disease
  • MEN 2A (60% of MEN2) associates medullary thyroid carcinoma (MTC) (100% of the cases) with pheochromocytoma in 50% of cases and with primary hyperparathyroidism (pHPT) in 5 to 20% of cases.
  • MEN 2B (5% of MEN2) is characterized by the association of MTC (100% of the cases) with pheochromocytoma (about 50% of the cases) as well as a phenotype including skeletal abnormalities suggestive of Marfan syndrome and the presence of multiple mucosal neuroma ; no pHPT is found in MEN 2B. DISEASE
  • Familial MTC only (FMTC) represents 35% of MEN 2 and is characterized by the absence of other associations throughout the entire follow up.
  • Hirschprung's disease or aganglionosis (HSCR) is a frequent congenital intestinal malformation (1/5000 live births) characterized by the absence of neural crest-derived parasympathetic neurons of the hindgut.
  • Typical sporadic papillary thyroid carcinoma and chilhood papillary thyroid carcinoma linked to radiation exposure are associated with somatic RET/PTC rearrangements.
  • Prognosis The prognosis of MEN2 and FMTC is related to MTC: its depends mainly on the histopathological stage of the MTC disease.
      

    Breakpoints

     

    Other Solid tumors implicated (Data extracted from papers in the Atlas)

    Solid Tumors AmeloblastomID5945 MedulloblastomaID5065 rhab5004

    External links

    Nomenclature
    HGNC (Hugo)RET   9967
    Cards
    AtlasRETID76
    Entrez_Gene (NCBI)RET  5979  ret proto-oncogene
    GeneCards (Weizmann)RET
    Ensembl (Hinxton)ENSG00000165731 [Gene_View]  chr10:43572517-43622952 [Contig_View]  RET [Vega]
    ICGC DataPortalENSG00000165731
    AceView (NCBI)RET
    Genatlas (Paris)RET
    WikiGenes5979
    SOURCE (Princeton)NM_000323 NM_020629 NM_020630 NM_020975
    Genomic and cartography
    GoldenPath (UCSC)RET  -  10q11.21   chr10:43572517-43622952 +  10q11.2   [Description]    (hg19-Feb_2009)
    EnsemblRET - 10q11.2 [CytoView]
    Mapping of homologs : NCBIRET [Mapview]
    OMIM142623   155240   162300   164761   171300   171400   191830   209880   
    Gene and transcription
    Genbank (Entrez)AI472270 AJ844649 AK291807 AK294827 AW297789
    RefSeq transcript (Entrez)NM_000323 NM_020629 NM_020630 NM_020975
    RefSeq genomic (Entrez)AC_000142 NC_000010 NC_018921 NG_007489 NT_030059 NW_001837940 NW_004929371
    Consensus coding sequences : CCDS (NCBI)RET
    Cluster EST : UnigeneHs.350321 [ NCBI ]
    CGAP (NCI)Hs.350321
    Alternative Splicing : Fast-db (Paris)GSHG0003316
    Alternative Splicing GalleryENSG00000165731
    Gene ExpressionRET [ NCBI-GEO ]     RET [ SEEK ]   RET [ MEM ]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP07949 (Uniprot)
    NextProtP07949  [Medical]
    With graphics : InterProP07949
    Splice isoforms : SwissVarP07949 (Swissvar)
    Catalytic activity : Enzyme2.7.10.1 [ Enzyme-Expasy ]   2.7.10.12.7.10.1 [ IntEnz-EBI ]   2.7.10.1 [ BRENDA ]   2.7.10.1 [ KEGG ]   
    Domaine pattern : Prosite (Expaxy)CADHERIN_2 (PS50268)    PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_TYR (PS00109)   
    Domains : Interpro (EBI)Cadherin    Cadherin-like    Kinase-like_dom    Prot_kinase_dom    Protein_kinase_ATP_BS    Ser-Thr/Tyr_kinase_cat_dom    Tyr_kinase_AS    Tyr_kinase_cat_dom    Tyr_kinase_Ret_rcpt   
    Related proteins : CluSTrP07949
    Domain families : Pfam (Sanger)Cadherin (PF00028)    Pkinase_Tyr (PF07714)   
    Domain families : Pfam (NCBI)pfam00028    pfam07714   
    Domain families : Smart (EMBL)CA (SM00112)  TyrKc (SM00219)  
    DMDM Disease mutations5979
    Blocks (Seattle)P07949
    PDB (SRS)1XPD    2IVS    2IVT    2IVU    2IVV    2X2K    2X2L    2X2M    2X2U    4CKI    4CKJ   
    PDB (PDBSum)1XPD    2IVS    2IVT    2IVU    2IVV    2X2K    2X2L    2X2M    2X2U    4CKI    4CKJ   
    PDB (IMB)1XPD    2IVS    2IVT    2IVU    2IVV    2X2K    2X2L    2X2M    2X2U    4CKI    4CKJ   
    PDB (RSDB)1XPD    2IVS    2IVT    2IVU    2IVV    2X2K    2X2L    2X2M    2X2U    4CKI    4CKJ   
    Human Protein AtlasENSG00000165731
    Peptide AtlasP07949
    HPRD01266
    IPIIPI00013983   IPI00479572   IPI00816406   IPI00816502   IPI00946110   
    Protein Interaction databases
    DIP (DOE-UCLA)P07949
    IntAct (EBI)P07949
    FunCoupENSG00000165731
    BioGRIDRET
    IntegromeDBRET
    STRING (EMBL)RET
    Ontologies - Pathways
    QuickGOP07949
    Ontology : AmiGOMAPK cascade  ureteric bud development  neural crest cell migration  embryonic epithelial tube formation  protein tyrosine kinase activity  transmembrane receptor protein tyrosine kinase activity  receptor activity  calcium ion binding  protein binding  ATP binding  integral component of plasma membrane  protein phosphorylation  activation of cysteine-type endopeptidase activity involved in apoptotic process  homophilic cell adhesion  neuron cell-cell adhesion  signal transduction  transmembrane receptor protein tyrosine kinase signaling pathway  posterior midgut development  endosome membrane  positive regulation of neuron projection development  positive regulation of neuron maturation  peptidyl-tyrosine phosphorylation  peptidyl-tyrosine phosphorylation  regulation of cell adhesion  positive regulation of cell migration  membrane protein proteolysis  positive regulation of cell adhesion mediated by integrin  ureter maturation  response to drug  neuron maturation  receptor complex  membrane raft  positive regulation of cell size  positive regulation of transcription, DNA-templated  response to pain  enteric nervous system development  regulation of axonogenesis  retina development in camera-type eye  innervation  Peyer's patch morphogenesis  cellular response to retinoic acid  positive regulation of metanephric glomerulus development  lymphocyte migration into lymphoid organs  positive regulation of extrinsic apoptotic signaling pathway in absence of ligand  positive regulation of extrinsic apoptotic signaling pathway in absence of ligand  
    Ontology : EGO-EBIMAPK cascade  ureteric bud development  neural crest cell migration  embryonic epithelial tube formation  protein tyrosine kinase activity  transmembrane receptor protein tyrosine kinase activity  receptor activity  calcium ion binding  protein binding  ATP binding  integral component of plasma membrane  protein phosphorylation  activation of cysteine-type endopeptidase activity involved in apoptotic process  homophilic cell adhesion  neuron cell-cell adhesion  signal transduction  transmembrane receptor protein tyrosine kinase signaling pathway  posterior midgut development  endosome membrane  positive regulation of neuron projection development  positive regulation of neuron maturation  peptidyl-tyrosine phosphorylation  peptidyl-tyrosine phosphorylation  regulation of cell adhesion  positive regulation of cell migration  membrane protein proteolysis  positive regulation of cell adhesion mediated by integrin  ureter maturation  response to drug  neuron maturation  receptor complex  membrane raft  positive regulation of cell size  positive regulation of transcription, DNA-templated  response to pain  enteric nervous system development  regulation of axonogenesis  retina development in camera-type eye  innervation  Peyer's patch morphogenesis  cellular response to retinoic acid  positive regulation of metanephric glomerulus development  lymphocyte migration into lymphoid organs  positive regulation of extrinsic apoptotic signaling pathway in absence of ligand  positive regulation of extrinsic apoptotic signaling pathway in absence of ligand  
    Pathways : KEGGEndocytosis    Pathways in cancer    Thyroid cancer   
    Protein Interaction DatabaseRET
    Wikipedia pathwaysRET
    Gene fusion - rearrangments
    Rearrangement : COSMICTRIM33 [1p13.2]  -  RET [10q11.21]
    Rearrangement : TICdbCCDC6 [10q21.2]  -  RET [3p25.2]
    Rearrangement : TICdbGOLGA5 [14q32.12]  -  RET [14q32.2]
    Rearrangement : TICdbHOOK3 [8p11.21]  -  RET [18q21.33]
    Rearrangement : TICdbKIF5B [10p11.22]  -  RET [Xq28]
    Rearrangement : TICdbNCOA4 [10q11.23]  -  RET [12q13.13]
    Rearrangement : TICdbPCM1 [8p22]  -  RET [1p22.3]
    Rearrangement : TICdbPRKAR1A [17q24.2]  -  RET [1q21.3]
    Rearrangement : TICdbTRIM27 [6p22.1]  -  RET []
    Polymorphisms : SNP, mutations, diseases
    SNP Single Nucleotide Polymorphism (NCBI)RET
    SNP (GeneSNP Utah)RET
    SNP : HGBaseRET
    Genetic variants : HAPMAPRET
    1000_GenomesRET 
    ICGC programENSG00000165731 
    Cancer Gene: CensusRET 
    CONAN: Copy Number AnalysisRET 
    Somatic Mutations in Cancer : COSMICRET 
    LOVD (Leiden Open Variation Database)Whole genome datasets
    LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
    LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
    LOVD (Leiden Open Variation Database)Mendelian genes
    LOVD (Leiden Open Variation Database)Zhejiang University Center for Genetic and Genomic Medicine (ZJU-CGGM)
    LOVD (Leiden Open Variation Database)MSeqDR-LSDB Mitochondrial Disease Locus Specific Database
    DECIPHER (Syndromes)10:43572517-43622952
    Mutations and Diseases : HGMDRET
    OMIM142623    155240    162300    164761    171300    171400    191830    209880   
    MedgenRET
    GENETestsRET
    Disease Genetic AssociationRET
    Huge Navigator RET [HugePedia]  RET [HugeCancerGEM]
    Genomic VariantsRET  RET [DGVbeta]
    Exome VariantRET
    dbVarRET
    ClinVarRET
    snp3D : Map Gene to Disease5979
    DGIdb (Curated mutations)RET
    DGIdb (Drug Gene Interaction db)RET
    General knowledge
    Homologs : HomoloGeneRET
    Homology/Alignments : Family Browser (UCSC)RET
    Phylogenetic Trees/Animal Genes : TreeFamRET
    Chemical/Protein Interactions : CTD5979
    Chemical/Pharm GKB GenePA34335
    Clinical trialRET
    Cancer Resource (Charite)ENSG00000165731
    Other databases
    Probes
    Litterature
    PubMed499 Pubmed reference(s) in Entrez
    CoreMineRET
    GoPubMedRET
    iHOPRET

    Bibliography

    Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains.
    Takahashi M, Buma Y, Iwamoto T, Inaguma Y, Ikeda H, Hiai H
    Oncogene. 1988 ; 3 (5) : 571-578.
    PMID 3078962
     
    Human ret proto-oncogene mapped to chromosome 10q11.2.
    Ishizaka Y, Itoh F, Tahira T, Ikeda I, Sugimura T, Tucker J, Fertitta A, Carrano AV, Nagao M
    Oncogene. 1989 ; 4 (12) : 1519-1521.
    PMID 2687772
     
    Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.
    Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L
    Nature. 1993 ; 363 (6428) : 458-460.
    PMID 8099202
     
    Mutations of the RET proto-oncogene in Hirschsprung's disease.
    Edery P, Lyonnet S, Mulligan LM, Pelet A, Dow E, Abel L, Holder S, Nihoul-Fłękłętłę C, Ponder BA, Munnich A
    Nature. 1994 ; 367 (6461) : 378-380.
    PMID 8114939
     
    A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma.
    Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, HłĆppener JW, van Amstel HK, Romeo G
    Nature. 1994 ; 367 (6461) : 375-376.
    PMID 7906866
     
    Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinoma.
    Marsh DJ, Learoyd DL, Andrew SD, Krishnan L, Pojer R, Richardson AL, Delbridge L, Eng C, Robinson BG
    Clinical endocrinology. 1996 ; 44 (3) : 249-257.
    PMID 8729519
     
    RET receptor expression in thyroid follicular epithelial cell-derived tumors.
    Bunone G, Uggeri M, Mondellini P, Pierotti MA, Bongarzone I
    Cancer research. 2000 ; 60 (11) : 2845-2849.
    PMID 10850426
     
    The RET proto-oncogene in human cancers.
    Jhiang SM
    Oncogene. 2000 ; 19 (49) : 5590-5597.
    PMID 11114739
     
    The RET receptor: function in development and dysfunction in congenital malformation.
    Maniłę S, Santoro M, Fusco A, Billaud M
    Trends in genetics : TIG. 2001 ; 17 (10) : 580-589.
    PMID 11585664
     
    The GDNF/RET signaling pathway and human diseases.
    Takahashi M
    Cytokine & growth factor reviews. 2001 ; 12 (4) : 361-373.
    PMID 11544105
     
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    Contributor(s)

    Written10-2003Patricia Niccoli-Sire
    Service d'Endocrinologie, DiabŔte et Maladies MÚtaboliques, H˘pital de la Timone, 254, rue St Pierre, 13385 Marseille cedex 05, France

    Citation

    This paper should be referenced as such :
    Niccoli-Sire, P
    RET (Rearranged during transfection)
    Atlas Genet Cytogenet Oncol Haematol. 2004;8(1):7-9.
    Free online version   Free pdf version   [Bibliographic record ]
    URL : http://AtlasGeneticsOncology.org/Genes/RETID76.html

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    indexed on : Thu Dec 4 15:05:39 CET 2014

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