RET (REarranged during Transfection)

2020-06-01   Jean Loup Huret  , Sylvie Yau Chun Wan-Senon  

jean-loup.huret@atlasgeneticsoncology.org; sylvie.ycw@hotmail.com

Identity

HGNC
RET
LOCATION
10q11.21
LOCUSID
5979
ALIAS
CDHF12,CDHR16,HSCR1,MEN2A,MEN2B,MTC1,PTC,RET-ELE1
FUSION GENES
Show Gene Fusions

Abstract

Review on RET gene and protein, a membrane tyrosine kinase receptor involved in various cancers, including papillary thyroid carcinoma, lung cancer, breast cancer, colorectal cancer, salivary glands cancer, skin melanomas\/spitz tumors and soft tissue sarcomas, but also in inherited diseases, including multiple endocrine neoplasia type 2, familial medullary thyroid carcinoma, familial pheochromocytoma predisposition, Hirschsprung disease, congenital central hypoventilation syndrome and renal hypodysplasia\/aplasia 1.

DNA/RNA

Transcription

Transcript (hg38), including UTRs: chr10:43,077,069-43,127,504; Size: 50,436bp on strand +; coding region: chr10:43,077,259-43,126,754 Size: 49,496 bp, according to UCSC. RET has at least 6 transcripts. In the 2 splice variants coding for a protein NM8020630 (19 exons) and NM8020975 (20 exons). Exon nineteen is partly different: exon 19 Asp1014 - Phe1072: DYLDLAASTPSDSLIYDDGLSEEETPLVDCNNAPLPRALPSTWIENKLYGRISHAFTRF, versus exon 19 Asp1014 - Gly1063: DYLDLAASTPSDSLIYDDGLSEEETPLVDCNNAPLPRALPSTWIENKLYG and exon 20 Gly1063 - Ser1114: MSDPNWPGESPVPLTRADGTNTGFPRYPNDSVYANWMLSPSAAKLMDTFDS.

Proteins

Atlas Image
Figure 1: RET amino acids sequence with Cadherin-like, Cysteine-rich, Transmembrane and Protein kinase domains with activation loop and LDRE, DXD, GEGEFGK, HRD, and DFG motifs and tyrosines.

Description

There are three protein isoforms with 9 (RET9; short isoform, 1072 amino acids), 43 (RET43; middle isoform, 1106 amino acids), or 51 amino acids (RET51; long isoform, 1114 amino acids) from different splicing in C term.
RET is composed of an extracellular region (amino acids (aa) 29-635, coded by exons 1-10, and part of exon 11), a transmembrane region (aa 636-657, coded by part of exon 11), and a cytoplasmic region (aa 658-1114 or 1072, coded by part of exon 11, and exon 12-19 or 12-20) (Figures 1 and 2).
RET has a Signal peptide (aa 1-28). RET contains a region of RET previously reported as having similarity to cadherins and named "cadherin domain" in databases (aa 168-272, coded by part of exon 3 and part of exon 4) and a bipartite protein kinase domain separated by a hinge (aa 805-812); (aa 724-1016, coded by part of exon 12, exons 13-18, and part of exon 19).
However, a detailed study shows that there are four cadherin-like domains (CLD): CLD1: aa 28-156 (exon 2 and part of exon 3), CLD2 aa 166-272 (part exon 3 and part of exon 4), CLD3 aa 273-387 (part exon 4, exon 5 and part of exon 6), CLD4: aa 401-516 (part exon 6, exon 7 and beginning of exon 8), with spacer sequences between CLD1 and CLD2 and between CLD3 and CLD4 (Anders et al., 2001).
There is a cysteine-rich domain (CRD, aa 515-634, coded by exons 8, 9, 10 and beginning of exon-11), and a calcium-binding sites (CA domain, aa 229-380, coded by part of exon 4, exon 5 and part of exon 6). The cysteine- rich domain is important for receptor dimerization. The cadherin domain adopts a β -sandwich fold, and calcium-binding sites are formed in between adjacent cadherin domains by the LDRE motif (aa 229-232) of CLD2 and the DXD motifs of CLD3 (aa 264-266 and 300-302). Ca2+ binding is required for the interaction of RET with GDNF.
Tyrosines: Tyrosine kinases usually have one or two tyrosines in the activation loop, in the case of RET there are two, Y900 and Y905, within the RDVYEEDSYVKRSQG peptide, both of which can be phosphorylated. Activation loop: Y905 is required for the transforming activity and signaling of RET-MEN2A mutations. The transforming activity of RET-MEN2B implicates Y864 or Y952. Y1062 is a multidocking site that interacts with a number of transduction molecules including SHC1, GRB2, FRS2, DOK4 / DOK5, IRS1 / IRS2, and PDLIM7. (Anders et al., 2001; Kouvaraki et al., 2005).
Other sites:
- GEGEFGK glycine-rich loop: nucleotide-binding loop 731-737, binding ATP
- K758: ATP binding site.
- DFG 892-894 motif: magnesium-binding loop
- R897 and R912: activation loop.
- HRD motif (aa 871-874) is responsible for nucleophilic attack (kinases lacking the HRD arginine are not phosphorylated in the activation loop). Activation loop phosphorylation can counteract the positive charge of the arginine in the catalytic loop by the HRD motif.
- Leucine rich: aa 11-22.
Other remarkable sites according to Prosite:
- Protein kinase C phosphorylation sites: aa 65 (phosphoserine), 75 (phosphothreonine), 110 (S), 131 (S), 159 (S), 173 (S), 224 (S), 295 (T), 328 (T), 413 (S), 492 (T), 522 (S), 538 (T), 561 (S), 675 (T), 811 (S), 819 (S)
- cAMP- and cGMP-dependent protein kinase phosphorylation sites: 315 (T), 696 (S)
- Casein kinase II phosphorylation sites: 104 (S), 131 (S), 261 (T), 350 (T), 363 (S), 456 (T), 457 (T), 564 (T), 670 (S), 729 (T), 765 (S), 836 (S), 847 (T), 922 (S), 930 (T), 1022 (T), 1034 (S), 1055 (T), 1078 (T)
- Tyrosine kinase phosphorylation site 2: 1089-1096: RypnDsvY
- N-myristoylation sites (role in membrane targeting): 28, 74, 275, 446, 453, 506, 514, 535, 550, 588, 601, 607, 810, 828, 830, 831, 1082
- N-glycosylation sites: 98, 151, 199, 336, 343, 361, 367, 377, 394, 448, 468, 554, 834, 975, 1092
- Amidation site XGRK (protects from proteolysis): 884-887.
Atlas Image
Figure 2: RET gene and protein

Expression

RET is particularly expressed in neural tissues (brain and autonomic nervous system: enteric, sympathetic, and parasympathetic), neuroendocrine cells, including thyroid C cells, adrenal medullary cells, parathyroid cells and in the developing kidney, but also in lung, digestive tract, adult kidney, female organs, male organs, skin, and blood apparatus.
Atlas Image
Figure 3: RET Electron Microscopy Structure 29-270 correspond to the cadherin-like domains CLD1 and CLD2 (see figure 2), 554-1009 correspond to part of crd (cysteine-rich domain), TM (transmembrane domain), and most of the tyrosine kinase domains; 29-635 correspond to the extracellular domains of RET. Images are taken from PhosphoSitePlus and ModBase:

href=u00b2https://www.phosphosite.org//proteinAction?id=654&showAllSites=true>https://www.phosphosite.org//proteinAction?id=654&showAllSites=true and

Localisation

RET is localized predominantly in the plasma membrane and in the cytoplasm; RET is also localized in the nucleus, indicating that intact RET can translocate into the nucleus (Bagheri-Yarmand et al. 2015). RET staining shows strong signals in both the cytoplasm, Golgi apparatus and cell membrane, whereas Hirschsprung mutant RET shows less pronounced staining on the cell membrane and more closer to the nucleolus/endoplasmic reticulum (The Human Protein Atlas).

Function

Ligands: there are four possible ligands for RET: GDNF (glial cell line-derived neurotrophic factor), NRTN (neurturin), PSPN (persephin), and ARTN (artemin). A multimetric complex composed of RET, one of the four ligands above mentioned, and one of four different high affinity glycosyl-phosphatidylinositol-anchored co-receptors, named GDNF family receptor-alpha GFRA 1 to 4.
Co-receptors: the four RET ligands GDNF, NRTN, PSPN, and ARTN interact preferentially with GFRA1, GFRA2, GFRA3, and GFRA4, respectively. The ligand (e.g. NRTN) forms a homodimer with a cystine knot at its center and requires its co-receptor (e.g. GFRA2) to activate RET. The NRTN-GFRA2 complex is composed of a dimer of dimers with the NRTN homodimer at the center and two GFRA2 monomers attached (see figure 4). GFRAs are located in lipid rafts of the plasma membrane, and RET is recruited. GFRAs can come from the same cell as RET, or from a different cell. When the co-receptor is produced by the same cell as RET, it is termed cis signaling. When the co-receptor is produced by another cell, it is termed trans signaling. Cis and trans activation of RET can occur (Reactome).
RET binding: the NRTN-GFRA2 complex binds two copies of the RET extra cellular domain ("RET-ecd") (--> RET dimerization), thereby forming a heterohexamer. RET-ecd consists of four cadherin-like domains (RET-CLD1-4) and a cysteine-rich domain (RET-crd). RET-CLD2 and RET-CLD3 coordinate calcium ions that are critical for RET folding.
Signaling: RET dimerization results in tyrosine autophosphorylation on specific tyrosine residues. (e.g. GDNF-GFRA1-activated RET is autophosphorylated at tyrosine-sites, Y981, Y1015, Y1062, and Y1096 (Note: Y1096 in found only in RET51 isoform)). RET activates various signaling pathways, mainly through Y1062, such as PI3K/AKT/MTOR, RAS/RAF/MAPK, and JUN pathways to activate transcription factors, including EIF4EBP1, RPS6KB1, MYC, JUN, ATF1, ATF2, TP53) (Kouvaraki et al., 2005; Goodman et al., 2014; Bigalke et al., 2019).
The frequently mutated C634 in patients with MEN2A is part of the RET-crd, in which wild-type RET forms a disulfide bond with C630. The C634R mutation causes ligand-independent dimerization of RET (Goodman et al., 2014; Bigalke et al., 2019).
Phosphatases: Protein tyrosine phosphorylation is regulated by opposite activities of protein tyrosine kinases (PTKs) and phosphatases (PTPs). GDNF and GRB2 form a complex with the protein tyrosine phosphatase PTPRA. PTPRA dephosphorylates RET and inhibits the RET-RAS/RAF/MAPK signaling pathway. PTPRA also regulates the RET mutant found in MEN2A, whereas the MEN2B mutant is insensitive to PTPRA (Yadav et al., 2020). Other phosphatases are also known to balance the phosphorylation and oncogenic activity of RET: PTPRF, PTPN6 and PTPN11.
Feedback loop: ATF4 overexpression induces cell death. ATF4 promotes RET degradation and inhibits RET signaling pathways. In a feedback loop, RET represses expression of the ATF4 target proapoptotic genes PMAIP1 (known as NOXA) and BBC3 (PUMA) through phosphorylation-dependent degradation of ATF4 (Bagheri-Yarmand et al. 2015; Bagheri-Yarmand et al. 2017).
Atlas Image
Figure 4: RET Pathway. An homodimer of Ligand (either GDNF, NRTN, PSPN, or ARTN) binds an homodimer of co-factors GFRA 1 to 4). The complex binds two RET proteins, forming a heterohexamer. RET dimerization results in tyrosine autophosphorylation which induces signaling pathways, such as PI3K/AKT/MTOR, RAS/RAF/MAPK, and JUN pathways (Figure 4). Note the so-called JUN pathway is the following RAC1 --> MAP3K proteins (misnamed MAPKKK... or JNKKK,e.g "MEKK1" or "MEKK4" for MAP3K1 and MAP3K4) --> MAP2K proteins (also called MAPKK... or JNKK, e.g "MKK4" or "MKK7" for MAP2K4 and MAP2K7) --> MAPK proteins (MAPK... or JNK, e.g "p38" or "JNK" for MAPK14 and MAPK8). Various processes are stimulated or repressed such as autophagy, angiogenesis, ribosomes biogenesis, translation, survival, apoptosis, differentiation, migration ...

Mutations

Note

Gain of function mutations affecting the extracellular cysteine-rich domain of RET result in covalent dimerization and constitutively activation of the receptor. Loss of function mutations inactivate the signaling pathway. Note: if needed, see "Nomenclature for the description of mutations and other sequence variations"
RET role in the tumor microenvironment: The tumor microenvironment (TME) consists of extracellular matrix, mesenchymal cells (i.e., fibroblasts, pericytes, adipocytes and other stromal cells), immune-inflammatory cells, blood and lymphatic vessels particularly in the perineural environment. Activation of the RET pathway has been found to be responsible for high expression and activation of cancer-associated fibroblasts-related proinflammatory proteins including cytokines, chemokines and their receptors (e.g. CCL2, CXCR4, CXCL8 (also called IL8), CXCL12, CCL20, CSF1, CSF2RA (GM-CSF), CSF3 (G-CSF), IL1B, SPP1). Cancer-associated fibroblasts promote tumorigenesis and metastasis, tumor angiogenesis and recruitment of immune-inflammatory cells (reviews in Castellone and Melillo 2018; Mulligan 2019).
Atlas Image
Figure 5: RET Translocations t(Var;10)(Var;q11) 5 Partner / 3 RET

Germinal

Mutations in RET have been found in various closely related inherited diseases, namely: multiple endocrine neoplasia type 2A (MEN2A), multiple endocrine neoplasia type 2B (MEN2B), familial medullary thyroid carcinomas (FMTC), familial pheochromocytoma predisposition, Hirschsprung disease, congenital central hypoventilation syndrome, and renal hypodysplasia/aplasia 1 (see below).
MEN2A/ MEN2B/ FMTC: 199 variants are described in MEN2 database (https://arup.utah.edu/database/MEN2/MEN2_display.php), of which 82 are said pathogenic. Mutations are dispersed through exons 7 to 16, many of them occurring in exons 10 or 11, in the cysteine rich domain: C609, C611, C618, C620 (exon 10), C630, D631, C634, T636, K666, D707 (exon 11). Other mutations are E505 (exon 7), C515, C531, G533, G548 (exon 8), E768, L790, Q781 (exon 13), V804 (exon 14), A883, S891, S904 (exon 15), M918, R912 (exon 16). The more common disease phenotype-specific mutations found in MEN2 are: E768D, L790F, Y791F, S891A, V804M/L (FMTC) and A883F, M918T (MEN2B). M918T catalytic domain mutants enhances autophosphorylation kinetics. M918T is a well characterized MEN2 mutation, and it correlates with the most aggressive and consistent disease phenotype (i.e. MEN2B) (Plaza-Menacho, 2017).

Somatic

Kato et al., 2017 studied 4,871 diverse cancer cases. RET aberrations were identified in 88 cases (1.8%). It was an amplification in 25% of cases (rounded numbers), a mutation in 40%, a translocation/fusion gene in 30%. Although subgroups are very small, it can be noted that mutations were found in medullary thyroid carcinoma (80%, 4 of 5 cases), paraganglioma (25%, 1/4), anaplastic thyroid carcinoma (17%, 2/12), and urothelial carcinoma (17%, 1/6). translocations/fusion genes were found in lung carcinosarcoma (17%, 1/6), papillary thyroid carcinoma (9%, 2/23) and lung adenocarcinoma (4%, 16/412), and amplifications were found in fallopian tube adenocarcinoma (8%, 1/12), uterine carcinosarcoma (5%, 1/19), and duodenal adenocarcinoma (5%, 1/20).
According to the review by Subbiah and Cote, 2020, the frequencies of somatic RET translocations/fusion genes and mutations associated with oncogenesis are the following: medullary thyroid cancer: 60-90%, papillary thyroid cancer: 10-20%, urothelial carcinoma: 16.7%, basal cell carcinoma: 12.5%, meningioma: 5.6%, non-small cell lung carcinoma: 1-2%, ovarian epithelial carcinoma: 1.9%, esophageal carcinoma: 1.4%, colorectal carcinoma: 0.7%, gastric adenocarcinoma: 0.7% , melanoma: 0.7%, and breast carcinoma: 0.2%,
in a series of 32,989 advanced cancers RET alterations included 143 in-frame fusions found in 141 patients and 33 single-nucleotide variants (SNV) resulting in an amino acid substitution found in 29 patients. RET fusions were most prevalent among patients with non-small cell lung carcinoma (NSCLC), thyroid cancer, or colorectal cancer. Seven different fusion partners (KIF5B, CCDC6, NCOA4, TRIM24, TRIM33, ERC1, APAF1) were observed. The most common fusion partner was KIF5B, which was only observed in NSCLC (n = 75) (Rich et al., 2019).
Copy number variations according to Genomic Data Commons Data Portal are: CNV gains in: sarcomas (11% of cases, rounded numbers), ovarian serous cystadenocarcinoma (10%), lung squamous cell carcinoma (8%), bladder urothelial carcinoma (7%), breast carcinoma (6%), lung adenocarcinoma (6%), esophageal carcinoma (6%), cholangiocarcinoma (6%), uterine carcinosarcoma (5%), adrenocortical carcinoma (4%), head and neck squamous cell carcinoma (4%), gastric adenocarcinoma (3%), hepatocellular carcinoma (3%), glioblastoma multiforme (3%), uterine endometrial carcinoma (2%), cervical carcinoma (2%), skin cutaneous melanoma (2%), colorectal adenocarcinoma (1-2%), pancreatic adenocarcinoma (1 %); CNV losses in: ovarian serous cystadenocarcinoma (9%), sarcomas (6%), uterine carcinosarcoma (5 %), bladder urothelial carcinoma (5%), mesothelioma (4%), esophageal carcinoma (3%), prostate adenocarcinoma (3%), breast carcinoma (3%), adrenocortical carcinoma (2%), uterine endometrial carcinoma (2%), head and neck squamous cell carcinoma (2%),cervical carcinoma (2%), gastric adenocarcinoma (2%), lung adenocarcinoma (1%), colon adenocarcinoma (1%), hepatocellular carcinoma (1%), lung squamous cell carcinoma (1%).
Kohno et al, 2020 reviewed the mutations and fusion genes involving RET in various cancers detected in two large studies (Project Genie and TCGA PanCancer Atlas Studies):
Mutations: medullary thyroid carcinoma: 55% of cases presented a mutation in RET; breast carcinoma: 8%; of cases parathyroid carcinoma: 6 %; pheochromocytoma: 3.4 - 4.0%; T-cell lymphoblastic leukemia: 3%; lung carcinoma (neuroendocrine): 3%; upper tract urothelial carcinoma: 0,4%; uterine endometrioid carcinoma (serous/papillary serous): 0,3%.
Translocations/fusion genes: RET translocations/fusion genes result in hybrid genes and proteins (Figure 5) with constitutive dimerization and activation of RET pathways. RET translocations/fusion genes were found in: papillary thyroid carcinoma, where 1.4 - 4.4% of cases presented a gene fusion implicating RET; poorly differentiated thyroid carcinoma: 3% of cases; pleomorphic lung carcinoma: 2.5%; thyroid carcinoma (hurthle cell): 2%; anaplastic thyroid carcinoma: 1%; lung adenocarcinoma: 0.2 - 0.6%; poorly differentiated non-small cell lung carcinoma: 0.5%; colon adenocarcinoma 0.26%; gastric adenocarcinoma 0.2%; serous ovarian carcinoma: 0,17%; non-small cell lung carcinoma: 0,16%.
TABLE 1: RET and 73 translocations/fusion partners
RET Partner GeneChrom.Location: band (bp)Translocation / fusion geneDisease
TRIM3311p13.2 (114392777)t(1;10)(p13;q11) TRIM33/RETLung: non-small cell lung carcinoma
Thyroid: papillary thyroid carcinoma
RASAL21q25.2 (178093729)t(1;10)(q25;q11) RASAL2/RETSoft tissue sarcoma
EML422p21 (42169338))t(2;10)(p21;q11) EML4/RETLung: non-small cell lung carcinoma
EML62p16.1 (54725012t(2;10)(p16;q11) EML6/RETLung: non-small cell lung carcinoma
TFG33q12.2 (100709331)t(3;10)(q12;q11) TFG/RETSoft tissues: spindle cell tumors
TBL1XR13q26.32 (177019355)t(3;10)(q26;q11) TBL1XR1/RETThyroid: papillary thyroid carcinoma
EPHA544q13.1 (65319563)t(4;10)(q13;q11) APHA5/RETLung: non-small cell lung carcinoma
SQSTM155q35.3 (179820842)t(5;10)(q35;q11) SQSTM1/RETThyroid: papillary thyroid carcinoma
KIF13A66p22.3 (17763693)t(6;10)(p22;q11) KIF13A/RETLung: adenocarcinoma
TRIM276p22.1 (28903002)t(6;10)(p22;q11) TRIM27/RETSalivary glands: intraductal carcinoma
Thyroid: papillary thyroid carcinoma
Neuro-endocrine tumor: multiple endocrine neoplasia
TBC1D326q22.31 (121079494)t(6;10)(q22;q11) TBC1D32/RETLung: adenocarcinoma
PTPRK6q22.33 (127968779)t(6;10)(q22;q11) PTPRK/RETLung: non-small cell lung carcinoma
FGFR1OP6q27 (166,999,317)t(6;10)(q27;q11) FGFR1OP/RETChronic myeloproliferative neoplasm
CLIP277q11.23 (74289475)t(7;10)(q11;q11) CLIP2/RETSoft tissues: spindle mesenchymal neoplasm
CUX17q22.1 (101817602)t(7;10)(q22,q11) CUX1/RETLung: non-small cell lung carcinoma
TRIM247q33 (138460334)t(7;10)(q33;q11) TRIM24/RETLung: non-small cell lung carcinoma
Thyroid: papillary thyroid carcinoma
TAS2R387q34 (141972631)t(7;10)(q34;q11) TAS2R38/RETThyroid: papillary thyroid carcinoma
PCM188p22 (17922857)t(8;10)(p22;q11) PCM1/RETLung: non-small cell lung carcinoma
Thyroid: papillary thyroid carcinoma
RBPMS8p12 (30384501)t(8;10)(p12;q11) RBPMS/RETLung: non-small cell lung carcinoma
HOOK38p11.21 (42896890)t(8;10)(p11;q11) HOOK3/RETThyroid: papillary thyroid carcinoma
FKBP1599q32 (113165520)t(9;10)(q32;q11) FKBP15/RETThyroid: papillary thyroid carcinoma
PRKCQ1010p15.1 (6427143)t(10;10)(p15;q11) PRKCQ/RETLung: non-small cell lung carcinoma
TAF3 10p14 (7818504)t(10;10)(p14;q11) TAF3/RETThyroid: papillary thyroid carcinoma
CCDC310p13 (12896625)t(10;10)(p13;q11) CCDC3/RETLung: non-small cell lung carcinoma
PRPF1810p13 (13586939)t(10;10)(p13;q11) PRPF18/RETLung: non-small cell lung carcinoma
FRMD4A10p13 (13643706)t(10;10)(p13;q11) FRMD4A/RETLung: non-small cell lung carcinoma
KIAA121710p12.2 (24208791)t(10;10)(p12;q11) KIAA1217/RETLung: adenocarcinoma
Soft tissues: spindle mesenchymal neoplasm
ANKRD2610p12.1 (27004116) t(10;10)(p12,q11) ANKRD26/RETThyroid: papillary thyroid carcinoma
ACBD510p12.1 (27195214)t(10;10)(p12;q11) ACBD5/RETThyroid: papillary thyroid carcinoma
WAC10p12.1 (28533492)t(10;10)(p12;q11) WAC/RETLung: non-small cell lung carcinoma
ARHGAP1210p11.22 (31805398)t(10;10)(p11;q11) ARHGAP12/RETLung: non-small cell lung carcinoma
KIF5B10p11.22 (32009010 )t(10;10)(p11;q11) KIF5B/RETLung: non-small cell lung carcinoma
Skin: melanomas/Spitz tumors
Thyroid: papillary thyroid carcinoma
PARD310p11.22 (34109560)t(10;10)(p11;q11) PARD3/RETLung: non-small cell lung carcinoma
CCNYL210q11.21 (42408174)CCNYL2/RET (10q11)Lung: non-small cell lung carcinoma
RASGEF1A10q11.21 (43194533)RASGEF1A/RET (10q11)Breast cancer
RASSF410q11.21 (44959771)RASSF4/RET (10q11)Lung: non-small cell lung carcinoma
NCOA410q11.23 (46005088)NCOA4/RET (10q11)Breast cancer
Colorectal cancer 
Lung: adenocarcinoma
Ovary: Germ cell tumours 
Salivary glands: intraductal carcinoma
Soft tissues: spindle cell tumors
Thyroid: papillary thyroid carcinoma
PRKG110q11.23 (51074474)PRKG1/RET (10q11)Lung: non-small cell lung carcinoma
ANK310q21.2 (60026298)t(10;10)(q11;q21) ANK3/RETThyroid: papillary thyroid carcinoma
SLC16A9 10q21.2 (59650764)t(10;10))(q11;q21) SLC16A9/RETThyroid: papillary thyroid carcinoma
CCDC610q21.2 (59788748)t(10;10)(q11;q21) CCDC6/RETColorectal cancer 
Lung: non-small cell lung carcinoma
Thyroid: papillary thyroid carcinoma
CTNNA310q21.3 (65912518)t(10;10)(q11;q21) CTNNA3/RETLung: non-small cell lung carcinoma
SIRT110q21.3 (67884669)t(10;10)(q11;q21) SIRT1/RETLung: non-small cell lung carcinoma
RUFY210q21.3 (68343518)t(10;10)(q11;q21) RUFY2/RETLung: non-small cell lung carcinoma
Thyroid: papillary thyroid carcinoma
DYDC110q23.1 (80336106)t(10;10)(q11;q23) DYDC1/RETLung: non-small cell lung carcinoma
SORBS110q24 (110005804)t(10;10)(q11;q24) SORBS1/RETLung: non-small cell lung carcinoma
ADD310q25.1 (114161608)t(10;10)(q11;q25) ADD3/RETLung: non-small cell lung carcinoma
CCDC18610q25.3 (114294824)t(10;10)(q11;q25) CCDC186/RETLung: non-small cell lung carcinoma
AFAP1L210q25.3 (126905409)t(10;10)(q11;q25) AFAP1L2/RETThyroid: papillary thyroid carcinoma
DOCK110q26.2 (126905409)t(10;10)(q11;q26) DOCK1/RETLung: non-small cell lung carcinoma
CLRN310q26.2 (127877841)t(10;10)(q11;q26) CLRN3/RETThyroid: papillary thyroid carcinoma
PPFIBP21111p15.4 (7513765)t(10;11)(q11;p15) PPFIBP2/RETThyroid: papillary thyroid carcinoma
PICALM11q14.2 (85957171)t(10;11)(q11;q14) PICALM/RETLung: non-small cell lung carcinoma
ETV61212p13.2 (11649854)t(10;12)(q11;p13) ETV6/RETSalivary glands: mammary analog secretory carcinoma
ERC112q13.33 (991208 )t(10;12)(q11;q13) ERC1/RETBreast cancer
Lung: non-small cell lung carcinoma
Thyroid: papillary thyroid carcinoma
ANKS1B12q23.1 (98743974)t(10;12)(q11;q23) ANKS1B/RETLung: non-small cell lung carcinoma
CLIP112q24.31 (122271434)t(10;12)(q11;q24) CLIP1/RETLung: non-small cell lung carcinoma
TSSK41414q12 (24205720)t(10;14)(q11;q12) TSSK4/RETLung: non-small cell lung carcinoma
KTN114q22.3 (55580207)t(10;14)(q11;q22) KTN1/RETThyroid: papillary thyroid carcinoma
CCDC88C14q32.11 (91271323)t(10;14)(q11;q32) CCDC88C/RETLung: non-small cell lung carcinoma
GOLGA514q32.12 (92794231)t(10;14)(q11;q32) GOLGA5/RETSkin: melanomas/Spitz tumors
Thyroid: papillary thyroid carcinoma
MYO5C1515q21.2 (52192318)t(10;15)(q11;q21) MYO5C/RETLung: non-small cell lung carcinoma
AKAP1315q25.3 (85380616)t(10;15)(q11;q25) AKAP13/RETThyroid: papillary thyroid carcinoma
MYH101717p13.1 (8474205)t(10;17)(q11;p13) MYH10/RETSoft tissues: Infantile myofibromatosis
Soft tissues: spindle mesenchymal neoplasm
MYH1317p13.1 (10300866)t(10;17)(q11;p13) MYH13/RETThyroid: papillary thyroid carcinoma
MPRIP17p11.2 (17042760)t(10;17)(q11;p11) MPRIP/RETLung: non-small cell lung carcinoma
PRKAR1A17q24.2 (68512379)t(10;17)(q11;q24) PRKAR1A/RETLung: non-small cell lung carcinoma
Neuro-endocrine tumor
RELCH (KIAA1468)1818q21.33 (62187291)t(10;18)(q11;q21) KIAA1468/RETLung: adenocarcinoma
Lung: non-small cell lung carcinoma
Thyroid: papillary thyroid carcinoma
LSM14A1919q13.11 (34172447)t(10;19)(q11;q13) LSM14A/RETLung: adenocarcinoma
RRBP12020p12.1 (17613678)t(10;20)(q11;p12) RRBP1/RETColorectal cancer 
BCR2222q11.23 (23180365)t(10;22)(q11;q11) BCR/RET Chronic myeloproliferative neoplasm
SPECC1L22q11.23 (24270817)t(10;22)(q11;q11) SPECC1L/RETThyroid: papillary thyroid carcinoma
TIMP322q12.3 (32800816)t(10;22)(q11 ;q12) TIMP3/RETSoft tissues: Inflammatory myofibroblastic tumor

Implicated in

Entity name
Multiple endocrine neoplasia type 2A (MEN2A)
Note
RET mutations in MEN2A are gain-of-function mutations.
Disease
Multiple endocrine neoplasia type 2A is an autosomal dominant syndrome of multiple endocrine neoplasms, including medullary thyroid carcinoma (MTC), a tumor of the calcitonin-secreting parafollicular C-cells in 100% of the cases, pheochromocytoma, a tumor of the adrenal chromaffin cells in 50% of the cases, and primary hyperparathyroidism in 20-30% of the cases. It is caused by missense mutations in RET. There is a cluster of mutations concerning six cysteines (aa 609, 611, 618, 620, exon 10 and aa 630, 634, exon 11, cysteine-rich domain) in MEN2A (Giraud, 2001; Somnay et al., 2012; Krampitz and Norton, 2014; Plaza-Menacho, 2017).
Entity name
Multiple endocrine neoplasia type 2B (MEN2B)
Note
RET mutations in MEN2B are gain-of-function mutations.
Disease
Multiple endocrine neoplasia type 2B, is an autosomal dominant syndrome defined by the presence of medullary thyroid carcinoma, pheochromocytomas, ganglioneuromatosis of the gastrointestinal tract, mucosal neuromas of the lips and tongue, and a Marfanoid habitus, but no hyperparathyroidism. It is caused by missense mutations in RET. The major mutation is M918T (coded by exon 16, tyrosine kinase domain) (Giraud, 2001; Somnay et al., 2012; Krampitz and Norton, 2014).
Entity name
Familial medullary thyroid carcinomas (FMTC)
Note
RET mutations in FMTC are gain-of-function mutations.
Disease
Medullary thyroid carcinomas (MTC) develop in either sporadic (75%) or hereditary form (25%). Familial Medullary thyroid carcinomas is an autosomal dominant syndrome of tumors of neuroendocrine origin that arise from para-follicular C cells which secrete a variety of peptides and hormones including calcitonin. FMTC can be an isolated condition, or part of MEN2A or MEN2B. It is caused by missense mutations in RET. Germline-activating RET mutations are found in 95%-98% of hereditary MTC, most often mutations in one of the 5 cysteines (aa 609, 611, 618, 620, exons 10 and aa 634, exon 11, cysteine-rich domain), mutations in aa 768, 790, 791, exon 14 or aa 804, 844 and aa 891, exon 15 being less frequent (in the tyrosine kinase domain). RET mutations are present in 25%-40% of sporadic MTC. Activating point mutations in RAS genes ( HRAS, KRAS, and NRAS) has been described in RET-negative sporadic MTC. Patients with a RET mutation had a worse outcome. The most frequent mutation in sporadic MTC was RET M918T (from c.2753T>C). RET C634W (from c.1902C>G) was also found frequently (Ceolin et al, 2012; Somnay et al., 2012; Krampitz and Norton, 2014; Ciampi et al., 2019).
Entity name
Familial pheochromocytoma predisposition
Note
RET mutations in familial pheochromocytoma predisposition are gain-of-function mutations.
Disease
Pheochromocytomas are adrenal medullary tumors (while paragangliomas arise from extra-adrenal ganglial sympathetic/parasympathetic chains) secreting catechocatecholamines with tachycardia, sweating and hypertension. It is an inherited form of cancer (autosomal dominant syndrome) in 10% to 25% of cases. In familial cases, pheochromocytoma is a component of one of the four following autosomal dominant syndromic diseases, Multiple Endocrine Neoplasia type 2, Von-Hippel-Lindau disease, hereditary paraganglioma syndrome and neurofibromatosis type 1. Pheochromocytoma is associated with germline and/or somatic mutations in more than 20 genes, mainly genes of the hypoxia-inducible factor (HIF) signaling pathway, succinate dehydrogenase genes and VHL, the kinase signaling pathway, including RET and RAS genes, and Wnt and Hedgehog pathways. In 75 to 90% cases, it is a sporadic or a non-syndromic disease of an unknown etiology (Gimenez-Roqueplo 2003; Jochmanova and Pacak, 2018).
RET mutations in pheochromocytoma are mainly found in exons 10, 11, 13 and 16. Carriers of codon 634 germline mutations present with much younger mean age of onset, and have a higher risk of developing pheochromocytomas.
Entity name
Hirschsprung disease
Note
RET mutations in Hirschsprung disease are loss of function mutations.
Disease
Hirschsprung disease or aganglionic megacolon is an autosomal dominant syndrome characterized by congenital absence of ganglion cells of the gastrointestinal tract (deficit in enteric nervous system), due to defective neural crest cell development. More than 10 genes are known to be possibly implicated in this disease, including RET, SOX10, ZEB2, EDNRB, EDN3 and PHOX2B.
Expression and penetrance of a RET mutation is variable and sex dependent (penetrance is 70% in males and 50% in females). More than 80 mutations have been identified, in particular: S32L, Y36C, L40P, P64L, L72P, R77C, G93S, L123F, A143G, C197Y, R231H, D264K, R287K, D300K, D300N, F329FfsX24, R330Q, R330N, R360W, P399L, R418X, D469N, R475Q, C611G, C620Y, all in the extracellular region (Anders et al., 2001; Butler Tjaden et al., 2013; Plaza-Menacho, 2017; Lorente-Ros et al., in press).
Entity name
Congenital central hypoventilation syndrome (CCHS)
Note
RET mutations in CCHS are loss of function mutations.
Disease
Congenital central hypoventilation syndrome (also called Haddad syndrome, Ondine-Hirschsprung disease), is a life-threatening syndrome characterized by impaired ventilatory response to hypercarbia and hypoxemia, Hirschsprung disease and tumors of neural-crest derivatives. It is sporadic in the majority of cases, and autosomal dominant in other cases, implicating PHOX2B, RET, GDNF, ASCL1 or EDN3 (Bolk et al., 1996; Amiel et al., 2003).
Entity name
Renal hypodysplasia/aplasia 1 (RHDA1)
Note
RET mutations in RHDA1 are loss of function mutations.
Disease
Renal hypodysplasia/aplasia 1 is an autosomal recessive syndrome which usually results in death in utero or in the perinatal period, and is associated with 3 genes ITGA8, PAX2, and RET according to LOVD. About 5% of living patients with congenital anomalies of the kidneys or lower urinary tract harbor mutations in the RET pathway, and RET mutations are present in 30% of fetuses with unilateral or bilateral renal agenesis. RET mutations or other alteration of the RET signaling pathway provokes delayed attachment of Wolffian duct to reach the cloaca, delayed degeneration of the mesonephros, renal agenesis or cystic dysplastic kidneys and ureters (Davis et al., 2014).
Entity name
Thyroid cancers
Disease
Thyroid cancer includes papillary thyroid carcinoma (PTC, 80% of thyroid cancers), follicular thyroid carcinoma (FTC, 10%-15% of thyroid cancers), medullary thyroid cancer (MTC, 5%-8% of thyroid cancers), and anaplastic thyroid cancer (less than 5%). Squamous and mucoepidermoid carcinomas account for 1% and 0.5 % of thyroid carcinomas.
RET translocations/fusion genes have been described in 20-40% of patients with papillary thyroid carcinoma, with higher frequency in radiation-exposed patients and mutations in RET have been reported in 40-70% of patients with medullary thyroid carcinoma (Kato et al., 2017)
Oncogenesis
RET polymorphisms and thyroid cancer: G691S, L769L and S904S polymorphisms were associated with predisposition to the development of sporadic MTC (Ceolin et al, 2012).
Medullary thyroid cancer: Amplification: 30% of medullary thyroid carcinomas harbour RET gene amplification with no alterations in chromosome 10 or a polysomy of chromosome 10, in variable percentage of cells, suggesting cell heterogeneity. RET copy number alterations can be considered a poor prognostic factor potentiating the poor prognostic role of RET mutation (Ciampi et al., 2012). Mutations: The far most frequent mutation in medullary thyroid cancer is M918T. Other mutations are: D631_L633delinsE, D631_L633delinsA, E632_L633del, C634R (cBioPortal). ATF4 promotes RET degradation. Low ATF4 expression correlates with poor overall survival of patients with MTC (Bagheri-Yarmand et al. 2017).
Papillary thyroid cancer: The most common rearrangements are translocation/fusion gene t(10;10)(q11;q21) CCDC6/RET and fusion gene NCOA4/RET, accounting for about 90%. Translocations/fusion genes in papillary thyroid cancer: t(1;10)(p13;q11) TRIM33/RET, t(3;10)(q26;q11) TBL1XR1/RET, t(5;10)(q35;q11) SQSTM1/RET, t(6;10)(p22;q11) TRIM27/RET, t(7;10)(q33;q11) TRIM24/RET, t(7;10)(q34;q11) TAS2R38/RET, t(8;10)(p22;q11) PCM1/RET, t(8;10)(p11;q11) HOOK3/RET, t(9;10)(q32;q11) FKBP15/RET, t(10;10)(p14;q11) TAF3/RET, t(10;10)(p12,q11) ANKRD26/RET, t(10;10)(p12;q11) ACBD5/RET, t(10;10)(p11;q11) KIF5B/RET, t(10;11)(q11;p15) PPFIBP2/RET, NCOA4/RET (10q11), t(10;10)(q11;q21) ANK3/RET, t(10;10))(q11;q21) SLC16A9/RET, t(10;10)(q11;q21) CCDC6/RET, t(10;10)(q11;q21) RUFY2/RET, t(10;10)(q11;q25) AFAP1L2/RET, t(10;10)(q11;q26) CLRN3/RET, t(10;12)(q11;q13) ERC1/RET, t(10;14)(q11;q22) KTN1/RET, t(10;14)(q11;q32) GOLGA5/RET, t(10;15)(q11;q25) AKAP13/RET, t(10;17)(q11;p13) MYH13/RET, t(10;18)(q11;q21) RELCH/RET, t(10;22)(q11;q11) SPECC1L/RET (PMID 8634704, 10337992, 10439047, 10741739, 10850414, 10980597, 11156407, 16946010, 17639057, 25175022, 25204415, 25417114, 25500544, 25546157, 27683183, 28351223, 28911147, 30466862, 31425920, 31715421 and data from Atlas Band 10q11 ).
Poorly differentiated thyroid cancer: mutation A1105V was found, and also translocations/fusion genes t(3;10)(q12;q11)TFG/RET, t(3;10)(q26;q11) PDCD10/RET and t(10;10)(q11;q21) CCDC6/RET.
Entity name
Lung cancers
Disease
Non-small cell lung carcinomas (NSCLC) are classified as: adenocarcinomas (30-40% of lung tumors), squamous cell carcinomas (40% of tumors), adenosquamous carcinomas, large cell carcinomas, sarcomatoid carcinomas, carcinoid tumors, and salivary gland tumors. Small cell lung carcinoma (SCLC), 20% of tumors, is a pulmonary neuroendocrine tumor. Other neuroendocrine tumors of the lungs are large cell neuroendocrine carcinomas, typical carcinoids, and atypical carcinoids.
RET translocations/fusion genes have been reported in 1% to 2% of patients with non-small cell lung cancer. Most cases of RET fusion-positive NSCLCs are adenocarcinoma, although Cai et al., 2013 screening 392 patients with NSCLC found 6 patients (1.5%) with a KIF5B/RET fusion: 4 had adenocarcinoma, 1 had a malignant neuroendocrine tumor, and 1 had squamous cell carcinoma. However, a meta-analysis of 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States was conducted. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%); squamous cell (1%) and advanced disease (91%). The most frequent rearrangement was KIF5B/RET (72%); CCDC6/RET was found in 19 patients (23%), NCOA4/RET in two patients (2%), EPHA5/RET in one patient (1%), and PICALM/RET in one patient (1%) (Gautschi et al., 2017). In a study screening 1139 lung adenocarcinoma patients, ALK fusions were detected in 5.1% of cases, RET fusions in 1.3%, and ROS1 fusions in 1%. No significant difference in survival was observed between fusion-positive and fusion-negative patients (Pan el al., 2014). RET mutations in small-cell (neuroendocrine) lung cancer is extremely rare (Rudin et al., 2014).
Oncogenesis
Cells expressing oncogenic KIF5B/RET are sensitive to multi-kinase inhibitors that inhibit RET (Lipson et al., 2012).
A study on non-small-cell lung cancer showed RET amplification in 3%, low RET gene copy number gain in 8%, and RET over expression in 8% of cases (Platt et al., 2015).
RET translocations/fusion genes in NSCLC: t(1;10)(p13;q11) TRIM33/RET, t(2;10)(p21;q11) EML4/RET, t(2;10)(p16;q11) EML6/RET, t(4;10)(q13;q11) APHA5/RET, t(6;10)(p22;q11) KIF13A/RET, t(6;10)(q22;q11) TBC1D32/RET, t(6;10)(q22;q11) PTPRK/RET, t(7;10)(q22,q11) CUX1/RET, t(7;10)(q33;q11) TRIM24/RET, t(8;10)(p22;q11) PCM1/RET, t(8;10)(p12;q11) RBPMS/RET, t(10;10)(p13;q11) CCDC3/RET, t(10;10)(p13;q11) PRPF18/RET, t(10;10)(p13;q11) FRMD4A/RET, t(10;10)(p12;q11) KIAA1217/RET, t(10;10)(p12;q11) WAC/RET, t(10;10)(p11;q11) PRKCQ/RET, t(10;10)(p11;q11) ARHGAP12/RET, t(10;10)(p11;q11), KIF5B/RET, t(10;10)(p11;q11) PARD3/RET, CCNYL2/RET (10q11), RASSF4/RET (10q11), NCOA4/RET (10q11), PRKG1/RET (10q11), t(10;10)(q11;q21) CCDC6/RET, t(10;10)(q11;q21) CTNNA3/RET, t(10;10)(q11;q21) SIRT1/RET, t(10;10)(q11;q21) RUFY2/RET, t(10;10)(q11;q23) DYDC1/RET, t(10;10)(q11;q24) SORBS1/RET, t(10;10)(q11;q25) ADD3/RET, t(10;10)(q11;q25) CCDC186/RET, t(10;10)(q11;q26) DOCK1/RET, t(10;11)(q11;q14) PICALM/RET, t(10;12)(q11;q13) ERC1/RET, t(10;12)(q11;q23) ANKS1B/RET, t(10;12)(q11;q24) CLIP1/RET, t(10;14)(q11;q12) TSSK4/RET, t(10;14)(q11;q32) CCDC88C/RET, t(10;15)(q11;q21) MYO5C/RET, t(10;17)(q11;p11) MPRIP/RET, t(10;17)(q11;q24) PRKAR1A/RET, t(10;18)(q11;q21) KIAA1468/RET, t(10;19)(q11;q13) LSM14A/RET (PMID 22327623, 23150706, 23533264, 27150058, 28115111, 28851076, 29571998, 29935851, 30429449, 30579554, 32127187, 32216946, Ignatius Ou and Zhu, in press, and data from Atlas Band 10q11).
mutations in lung adenocarcinoma: L56M, E61K, T75K, R77C, R77L, H103N, L109I, X113_splice, K124*, E164K, P181H, E251Q, D290N, R297L, T350N, H352P, R355M, Q371K, V374M, L375Q, S406R, X421_splice, E428G, G453W, D460V, A479S, M484T, R494M, A496G, G506W, A510S, A513E, C541F, P560H, P566T, D567Y, X587_splice, G588D, G593R, C611S, V648I, F719L, P720L, V739F, V755L, V757M, M759I, N763K, P766Q, L790*, G798V, A807P, R817H, D839N, M848V, Q860P, S891*, E901K, S932N, E978Q, E1006*, M1009K, R1013K, D1031Y, L1048Pfs*11, E1072K, dispersed through all the RET length.
mutations in lung squamous cell carcinoma, according to cBioPortal: R33Kfs*29, A59S, R114S, R114H, E235Q, M255I, W324C, E366*, S462L, E530*, T564N, G691Vfs*40, A756G, E775Sfs*5, F776S, G825C, W856L, W917R, A919S, V934=, W942S, P951S, E979Q, R1013T, V1095.
Entity name
Breast carcinoma
Note
The treatment-relevant subtypes of invasive carcinoma are based on "ER" (estrogen receptors ESR1 and ESR2), "PR" (progesterone receptor PGR) and "HER2" (ERBB2) status: ER+, ER-, PR+, PR-, HER2+, HER2-. Last, ER-/PR-/HER2- are called basal-like or triple negative breast cacinoma.
Oncogenesis
Tumor-specific expression of GDNF and ARTN is relatively frequent and can promote autocrine activation of RET downstream signaling. RET is an estrogen receptor target gene. IL6 and RET form a positive feed-forward loop that stimulates migration. ET activation increases migration and proliferation of ER+ (estrogen receptor +) breast cancer. Elevated RET levels are found not only in ER+ tumors, but in other sub-types of human breast cancer and correlate with decreased metastasis-free survival and poor prognosis in breast cancer patients. RET alterations (amplifications/copy number gains, mutations or chromosome rearrangements) were found in 1.2% in a large cohort of 9693 breast cancers. RET amplifications were the most commonly observed and mainly found in ER- and HER2- breast cancers, followed by missense mutations and rearrangements. RET missense mutations were more frequently associated with ER+ breast cancers. NCOA4/RET positive breast cancer responds to cabozantinib. Expression is higher in recurrent cancers and is correlated with larger tumor size, higher tumor stage and reduced metastasis-free and overall survival. RET expression in breast cancer is also correlated with resistance to endocrine therapies via stimulation of the PI3K/AKT/MTOR signaling pathway. Tyrosine kinase inhibitors could be useful treatments (Gattelli et al., 2013; Morandi et al., 2013; Hatem et al., 2016; Paratala et al., 2018; Mulligan 2019).
RET mutations: P117T, S148del, F195L, R330Q, R368C, A479T, P537Qfs*101, S518C, A604D, C611Y, I625M, C634R/G, F663Lfs*12, V778I, A793Pfs*76, G828A, D842H, L846I, I852M, M868I, M918T, P951Lfs*12, X934_splice L963V, E991*, L1101V, dispersed through all the RET length (cBioPortal); and translocations/fusion genes: t(10;12)(q11;q13) ERC1/RET, NCOA4/RET (10q11), RASGEF1A/RET (10q11) (Stransky et al., 2014; Paratala et al., 208; Rich et al., 2019).
Entity name
Epithelial ovarian cancer.
Oncogenesis
Genomic RET missense mutations was found in 2% of patients. These mutations were: D58N, R114H, R205S; G248S; A342G, T636M, A680T, G727V, G751V, K780N, N879S, N879D, N879S, X934_splice, R959W, A1105G, and K1107N. Patients with RET alterations had shorter progression-free survival than those without RET alterations. R693H and A750T mutants of RET enhance the signal transduction of RET, the cell viability and colony formation of cells, and the growth of tumor xenografts of ovarian cancer (Guan et al., 2020). Translocations/fusion gene: NCOA4/RET fusion was found in an ovarian germ cell tumour. As a matter of fact, it was a papillary thyroid carcinoma arising in struma ovarii (struma ovarii originate from ovarian germ cells) (Richardson and Mulligan, 2009). KIF5B/RET and CCDC6/RET fusion genes were also found (Kato et al., 2017; Gao et al., 2018).
Entity name
Uterine endometrioid carcinoma
Note
Endometrioid carcinoma is the most common endometrial cancer (75%), and endometrial carcinoma represents 95% of uterine corpus cancers. It is an epithelial neoplasia.
Oncogenesis
Mutations G115S, R133C, K161E, R180*, L196S, C197Y, T225M, A241V, E251K, P273T, R313W, T317M, R330Q, R348Q, A349V, A373V, A386V, S396L, R418*, I422=, T451M, R474W, A487V, E511D, V573M, P596H, E623K, A640V, S649L, I657S, A672S, A680T, R721W, E768G, A793D, R844Q, I858V, S891L, R912W, S936Y, R969W, C976Y, E978D, R982H, A999V, E1006D, L1018I, A1019V, G1063D, X1063_splice, N1092H, L1108*, D1110G, dispersed through all the RET length. RET high expression is an unfavorable prognostic marker in endometrial cancer (The Human Protein Atlas).
Entity name
Colorectal cancer
Disease
RET fusions have been described in less than 1% of colorectal cancers.
Oncogenesis
A study on 37 cases determined 4 cases with RET mutations/variants: R77C, P270L, G533C, P1047S. RET activating mutations identified in colon cancer patients increase anchorage-dependent cell proliferation and clonogenic cell survival. Variant G533C is clearly oncogenic whereas RET variant P1047S is not. Cells expressing the RET G533C mutant are sensitive to treatment with the RET specific inhibitor vandetanib (Mendes Oliveira et al., 2018). RET fusions were more frequent in older patients, right-sided tumors, MSI-high, RAS and BRAF wild-type. Patients with RET fusion-positive tumors showed a significantly worse overall survival (Pietrantonio et al., 2018). The following RET mutations were found: A4E, T48M, G74S, R77H, R79W, F126C, R133H, R175H, R177W, E235G, V245M, V260*, K288N, A306V, G321R, T328S, R360Q, A373V, R418*, R418Q, A432V, T451M, Y508H, E511K, R525W, X550_splice, D571N, E595K, Q703H, V706M, X712_splice, P715S, T742M, T754M, A756V, R770*, K789E, R817C, M848V, Q860R, E867A, R912W, P914S, P951A, R959W, T1022A, L1016F, T1055A (cBioPortal) and translocations/fusion genes were: NCOA4/RET (10q11), t(5;10)(q33;q11) TNIP1/RET, t(7;10)(q34;q11) TRIM24/RET, t(10;10)(q11;q21) CCDC6/RET, t(10;19)(q11;q13) SNRNP70/RET and t(10;20)(q11;p12) RRBP1/RET (Stransky et al., 2014; Le Rolle et al., 2015; Kloosterman et al., 2017; Pietrantonio et al., 2018).
Aberrant methylation of RET is found in colon adenomas and adenocarcinomas, and is associated with decreased RET expression, potentially leading to inhibition of RET-induced apoptosis of colon cancer cells (Li et al., 2019).
Entity name
Esophageal adenocarcinoma
Oncogenesis
Mutations E61K, Q187K, E238K, C565F, P582L, M848I, A1019V.
Entity name
Gastric adenocarcinoma
Oncogenesis
Mutations G69D, R205G, A279T, R287W, R313W, A349V, A432V, N448S, T451M, F466S, Q583*, P613L, V706M, R721Q, A793T, R817H, R820H, R833C, K907T, E921D, N950Tfs*15, E978K, M1009V, N1045S, A1046T. Fusion gene: CCDC6/RET.
Entity name
Pancreatic ductal adenocarcinoma
Oncogenesis
The common polymorphic variant G691S (polymorphism found in 30% of normal pancreas, allelic frequency of 15%) is over represented in pancreatic ductal adenocarcinomas patients (allelic frequency of 20%) Overexpression of G691S RET increased invasion of pancreatic cancer cells (Sawai et al., 2005). Activation of RET is capable of inducing invasive pancreatic carcinomas. RET mutations in pancreatic carcinomas, according to cBioPortal are: A4V, R57W, R57Q, V276I, F329L, A756D, R844W, R770*, R897*, P1070S.
Entity name
Leukemias
Oncogenesis
RET expression in acute myeloid leukemia is maturation-associated: RET gene expression occurs more frequently in AMLs displaying either a monocytic (M4/M5) or intermediate-mature myeloid phenotype (M2/M3) than in leukemias reflecting an earlier stage of myeloid differentiation (M0/M1). (Gattei et al., 1998). The following RET mutations found in leukemias were: G691S in acute myeloid leukemia, G691S, R982C in B-lymphoblastic leukemia, L816P in T-lymphoblastic leukemia, N336T in diffuse large B-cell lymphoma, G115S in mature B-cell neoplasm NOS, X587_splice in angioimmunoblastic T-cell lymphoma, G691S in peripheral T-cell lymphoma NOS (BioPortal). and the following translocations: a t(6;10)(q27;q11) FGFR1OP/RET and a t(10;22)(q11;q11) BCR/RET were found in chronic myelomonocytic leukemia and in primary myelofibrosis with secondary acute myeloid leukemia, and a t(9;10)(q32;q11) FKBP15/RET in acute myeloid leukemia NOS (Ballerini et al., 2012; Bossi et al., 2014; Gao et al., 2018).
Entity name
Bladder urothelial carcinoma
Oncogenesis
Mutations V245A, E337K, R348Q, E673K, R817C, E818D, E884K, G949Efs*16, F998L, A999E, M1009I, N1059D, D1081H, M1109I.
Entity name
Papillary renal cell carcinoma
Oncogenesis
Cytoplasmic and nuclear expression of RET are strong negative predictors of survival in papillary renal cell carcinoma (Li et al., 2019).
Entity name
Nervous system tumors
Oncogenesis
Astrocytoma : Mutations G47S, P182S, G435D, A807T, R813W, D1093G.
Glioblastoma multiforme : Mutations N113=, R133H, R133C, R171K, D219N, E289A, S339*, N361I, N437I, G546R, R635H, A682V, D892N.
Neuroblastoma (Peripheral neuroblastic tumours of the sympathetic nervous system, mainly found in infants and young children): RET was found to be highly expressed (Li et al., 2019).
Entity name
Head and neck squamous cell carcinoma
Oncogenesis
Mutations Q44H, V63M, N84S, E284Q, E337V, E366*, A373V, A386T, Y483D, C585S, E616del, C634Y, K740N, T946A.
Entity name
Salivary glands tumors
Oncogenesis
t(6;10)(p22;q11) TRIM27/RET, NCOA4/RET fusion and t(10;12)(q11;p13) ETV6/RET were found in intraductal carcinoma, invasive carcinoma and secretory carcinoma of the salivary glands (Skálová et al., 2018a; (Skálová et al., 2018b; Guilmette et al., 2018; Skálová et al., 2019).
Entity name
Prostate cancer
Oncogenesis
RET is expressed in prostate cancer cell lines established from advanced prostate cancers. RET is also expressed in about 20% of localized prostate adenocarcinomas as well as in small cell neuroendocrine cancers of the prostate. GDNF is expressed by nerves, and nerve fibers secrete GDNF in the peritumoral stroma in prostate cancer. GDNF/RET signaling can enhance proliferation, invasion in prostate cancers (Ban et al. 2017). RET was overexpressed in patients with neuroendocrine prostate cancer (VanDeusen et al. in press). The following RET mutations were found: R57W, R67C, T130I, V202M, A281T, V782I, R886W, A1046S and translocations/fusion genes were: NCOA4/RET fusion (cBioPortal).
Entity name
Skin neoplasms
Oncogenesis
RET G691S polymorphism is frequent in skin melanoma (found in 30% of the cases), particularly in desmoplastic subtypes (6%), compared to the general population (15-20%). The polymorphism was germline in 30% of the patients with desmoplastic melanomas and 21% of the patients with non-desmoplastic melanoma. RET G691S may be a genetic risk factor for the development of desmoplastic melanoma (Narita et al., 2009; Barr et al., 2012).
Mutations in squamous cell carcinoma : X25_splice, W85*, E107K, R114H, T120S, D547G, P599S, S705F, G736E, Y826F, Y826*, E843K, R844W, P957L.
Mutations in skin melanoma are the following: X25_splice, A55V, E62K, R67C, W85*, T92I, G141S, P155S, E208D, P259Q, X290_splice, G308V, E309K, P320S, D322N, W324L, E337K, A342V, E366Q, N367S, S379*, R417C, A472V, E480K, L481R, D627N, V685I, S696*, D698N, W717*, G736R, A741T, F744Y, H745N, G823ED839N, P841S, L851I, R873W, R897P, K907N, R912Q, S936F, M970I, D1000N, G1032D, E1036Q, P1049S, E1058K, D1093N, L1108* (cBioPortal).
Translocations in melanomas/ Spitz tumors were: t(10;10)(p11;q11) KIF5B/RET and t(10;14)(q11;q32) GOLGA5/RET (Wiesner et al., 2014).
Entity name
Soft tissue sarcomas
Disease
A t(7;10)(q11;q11) CLIP2/RET, a t(10;10)(p12;q11) KIAA1217/RET, and a t(10;17)(q11;p13) MYH10/RET were found in spindle mesenchymal neoplasms (Davis et al., 2020). A t(3;10)(q12;q11) TFG/RET and NCOA4/RET (10q11) were found in spindle cell tumors (Michal et al., 2019; Loong et al., 2020). A t(10;22)(q11;q12) TIMP3/RET was found in an inflammatory myofibroblastic tumor of the uterus (Cheek et al., 2020). A t(10;17)(q11;p13) MYH10/RET was found in an infantile myofibromatosis (Rosenzweig et al., 2017). A t(1;10)(q25;q11) RASAL2/RET was found in high-grade sarcoma (Zhou et al., 2020).
Entity name
Pediatric cancers
Note
RET gene fusions have been reported in 20% to 45% of papillary thyroid carcinomas and less frequently in pediatric and young adult patients with glioma and various pediatric soft tissue tumors. CSGALNACT2/RET fusion gene was found in a paediatric high grade glioma (Carvalho et al., 2014). A VCL/RET fusion gene was found in 7 year-old boy with lipofibromatosis, a rare pediatric soft tissue tumor (Al-Ibraheemi et al., 2019). Ortiz et al., 2020 described 5 patients: 2 cases of medullary thyroid cancer, aged 7yrs and 15yrs with RET mutation; a 7mth-old baby with infantile myofibroma/hemangiopericytoma and a MYH10/RET fusion gene; a 2mth-old baby with mesoblastic nephroma / infantile fibrosarcoma and a SPECC1L/RET fusion gene; and a case of lipofibromatosis presenting at birth with a NCOA4/RET fusion. Infantile myofibromatosis may also harbour RET chromosomal rearrangements see above).

Breakpoints

Atlas Image
Figure 6: RET Partners

Note

In a series of from 32,989 advanced cancers twenty-five different breakpoint combinations were observed, >95% of which involved intron 11 of RET, most commonly fused with intron 15 of KIF5B in 80%, intron 1 of CCDC6 in 90%, or intron 8 or 10 of NCOA4 in 36 and 57% respectively. KIF5B/RET translocations were highly specific for non-small cell lung carcinoma (Rich et al., 2019). Santoro et al., 2020 present a lovely representative scheme of RET and 50 fusion partners, indicating the most frequent breakpoint sites in partner proteins, and their domains retained in the fusion protein.
TABLE 2: Breakpoints according to Cosmic
Hybrid GenePartner Gene Last Exon Breakpoint RET RET First Exon Breakpoint Tissue
TRIM33/RET5 TRIM33 161_2976 3 RET 122369_5659 Thyroid (0.7%)
TRIM27/RET5 TRIM27 31_1104+6742 3 RET 122369-1668_5659 Thyroid (1.4%)
TRIM24/RET5 TRIM24 91_1745 3 RET 122369_5659Thyroid (0.7%)
PCM1/RET5 PCM1 291_5266 3 RET 122369_5659Thyroid (1.8%)
HOOK3/RET5 HOOK3 111_1322 3 RET 122369_5659 Thyroid (1.8%)
KIF5B/RET5 KIF5B 151_2183 3 RET 122369_5659 
5 KIF5B 161_2372 3 RET 122369_5659Skin 2.6%; Lung (1.5%)
NCOA4/RET5 NCOA4 81_907 3 RET 122369_5659 Thyroid (8%), Lung, Soft tissue
CCDC6/RET5 CCDC6 11_535 3 RET 122369_5659Thyroid (12.7%;) Lung 50.5%
ERC1/RET5 ERC1111_2338 3 RET 122369_5659Thyroid (1%)
KTN1/RET5 KTN1 291_2960 3 RET 122369_5659Thyroid (1.4%)
GOLGA5/RET5 GOLGA5 71_1747 3 RET 122369_5659Skin (2.6%); Thyroid (0.8%)
PRKAR1A/RET5 PRKAR1A71_825 3 RET 122369_5659Thyroid (2.7%)
RELCH/RET5 RELCH 101_1852 3 RET 122369_5659Lung (0.2%)

1p13 TRIM33/RET PMID 10439047, 11786418, 14668719
6p22 TRIM27/RET PMID 12787916, 14668719
7q33 TRIM24/RET PMID 10439047, 11786418, 14668719
8p22 PCM1/RET PMID 10980597, 14668719
8p11 HOOK3/RET PMID 14668719, 17639057
10p11 KIF5B/RET PMID 22194472, 22327622, 22327623, 22327624, 22797671, 23150706, 23418494, 23891510, 24133367, 24158231, 24346091, 24445538, 24469108, 24481316, 24700479, 24722163, 24727320, 24810493, 25348872
10q11 NCOA4/RET PMID 8180971, 8187085, 8290261, 8545102, 8806699, 8806700, 9001272, 9466701, 9482114, 9516913, 9528832, 9669285, 9935226, 10083732, 10675479, 10720057, 10773666, 10946873, 1111778111117782, 11443191, 11747322, 11786418, 11788677, 11927965, 12057919, 12720532, ,, 14668719, 15737050, 15788648, 15876154, 16015630, 16595592, 16784981, 17464312, 17727338, 17786355, 18226854, 18393128, 18757433, 19495791, 19958951, 20012784, 20099311, 20447069, 20564403, 20703476, 20712653, 20840674, 20924280, 21048359, 21173509, 21219595, 21411555, 21498916, 22481925, 22682753, 22745248, 22895275, 22961909, 23150706, 23436219, 23806056, 23966419, 24277231, 24417340, 24503805, 24613930, 24915144, 25111330, 26971368
10q21 CCDC6/RET PMID 2406025, 8545102, 8634704, 9001272, 9466701, 9508203, 9516913, 9528832, 9669285, 9935226, 10083732, 10675479, 10720057, 10773666, 10931090, 10946873, 10951397, 11117781, 11117782, 11443191, 11493988, 11747322, 11786418, 11788677, 11927965, 12057919, 12720532, 14668719, 15737050, 15788648, 15876154, 16015630, 16595592, 16784981, 17464312, 17727338, 17786355, 18226854, 18393128, 18757433, 19055826, 19495791, 19958951, 20012784, 20099311, 20447069, 20564403, 20703476, 20712653, 20840674, 20924280, 21048359, 21173509, 21219595, 21411555, 21498916, 22327623,22481925,22682753, 22745248, 22895275, 22961909, 23150706, 23436219, 23806056, 23966419, 24133367, 24158231, 24277231, 24327398, 24346091, 24417340, 24469108, 24503805, 24613930, 24700479, 24727320, 24810493, 24915144, 25111330, 25348872, 26187428, 26971368, 27588476
12q13 ERC1/RET PMID 10337992, 14668719, 15876154
14q22 KTN1/RET PMID 10850414, 11786418, 14668719, 18757433
14q32 GOLGA5/RET PMID 9443391, 10675479, 10773666, 11786418, 14668719, 24445538
17q24 PRKAR1A/RET PMID 7519046, 7678053, 8545102, 9466701, 9516913, 9528832, 9669285, 9935226, 10083732, 10675479, 10720057, 10773666, 10946873, 11117781, 11117782, 11747322, 11786418, 11788677, 14668719, 15876154, 18393128, 20447069, 22481925, 24277231
18q21 RELCH/RET PMID 24727320

Article Bibliography

Pubmed IDLast YearTitleAuthors

Other Information

Locus ID:

NCBI: 5979
MIM: 164761
HGNC: 9967
Ensembl: ENSG00000165731

Variants:

dbSNP: 5979
ClinVar: 5979
TCGA: ENSG00000165731
COSMIC: RET

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000165731ENST00000340058P07949
ENSG00000165731ENST00000355710P07949
ENSG00000165731ENST00000355710A0A024R7T2
ENSG00000165731ENST00000498820C9JYL6
ENSG00000165731ENST00000615310Q9BTX6
ENSG00000165731ENST00000638465A0A1W2PPN7
ENSG00000165731ENST00000640619A0A1W2PSA1

Expression (GTEx)

0
1
2
3
4
5
6
7
Adipose - Subcutaneous
Adipose - Visceral
Adrenal Gland
Artery - Aorta
Artery - Tibial
Bladder
Brain - Amygdala
Brain - Anterior cingulate cortex
Brain - Caudate
Brain - Cerebellar Hemisphere
Brain - Cerebellum
Brain - Cortex
Brain - Frontal Cortex
Brain - Hippocampus
Brain - Hypothalamus
Brain - Nucleus accumbens
Brain - Putamen
Brain - Spinal cord
Brain - Substantia nigra
Breast - Mammary Tissue
Cells - Cultured fibroblasts
Cells - EBV - transformed lymphocytes
Cervix - Ectocervix
Cervix - Endocervix
Colon - Sigmoid
Colon - Transverse
Esophagus - Gastroesophageal Junction
Esophagus - Mucosa
Esophagus - Muscularis
Fallopian Tube
Heart - Atrial Appendage
Heart - Left Ventricle
Kidney - Cortex
Kidney - Medulla
Liver
Lung
Minor Salivary Gland
Muscle - Skeletal
Nerve - Tibial
Ovary
Pancreas
Pituitary
Prostate
Skin - Not Sun Exposed
Skin - Sun Exposed
Small Intestine - Terminal Ileum
Spleen
Stomach
Testis
Thyroid
Uterus
Vagina
Whole Blood

Pathways

PathwaySourceExternal ID
Thyroid cancerKEGGko05216
Pathways in cancerKEGGhsa05200
Thyroid cancerKEGGhsa05216
EndocytosisKEGGko04144
EndocytosisKEGGhsa04144
Central carbon metabolism in cancerKEGGhsa05230
Central carbon metabolism in cancerKEGGko05230
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
RAF/MAP kinase cascadeREACTOMER-HSA-5673001
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GRB2 events in EGFR signalingREACTOMER-HSA-179812
SHC1 events in EGFR signalingREACTOMER-HSA-180336
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
SOS-mediated signallingREACTOMER-HSA-112412
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
Signalling to p38 via RIT and RINREACTOMER-HSA-187706
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
ARMS-mediated activationREACTOMER-HSA-170984
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFA-VEGFR2 PathwayREACTOMER-HSA-4420097
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
Signaling by GPCRREACTOMER-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Signaling by LeptinREACTOMER-HSA-2586552
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
NCAM signaling for neurite out-growthREACTOMER-HSA-375165
RET signalingREACTOMER-HSA-8853659

Protein levels (Protein atlas)

Not detected
Low
Medium
High
cerebral cortex
cerebellum
hippocampus
caudate
thyroid gland
parathyroid gland
adrenal gland
bronchus
lung
oral mucosa
salivary gland
esophagus
stomach 1
stomach 2
duodenum
small intestine
colon
rectum
liver
gallbladder
pancreas
kidney
urinary bladder
testis
epididymis
seminal vesicle
prostate
vagina
ovary
fallopian tube
endometrium 1
endometrium 2
cervix, uterine
placenta
breast
heart muscle
smooth muscle
skeletal muscle
soft tissue 1
soft tissue 2
adipose tissue
skin 1
skin 2
appendix
spleen
lymph node
tonsil
bone marrow

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA162372840sunitinibChemicalMultilinkAnnotationassociated19248971
PA165906891cabozantinibChemicalLabelAnnotationassociated
PA166118341vandetanibChemicalLabelAnnotation, Literature, MultilinkAnnotationassociated24433361
PA29444HRASGenePathwayassociated28362716
PA30196KRASGenePathwayassociated28362716
PA31768NRASGenePathwayassociated28362716
PA31817NTRK1GeneDataAnnotationassociated
PA445857Thyroid NeoplasmsDiseaseLiterature, MultilinkAnnotationassociated23788249
PA446649Carcinoma, MedullaryDiseaseDataAnnotationassociated
PA446772Multiple Endocrine Neoplasia Type 2aDiseaseDataAnnotationassociated
PA7000sorafenibChemicalPathwayassociated28362716

References

Pubmed IDYearTitleCitations
379217252024Impact of the overexpression of the tyrosine kinase receptor RET in the hematopoietic potential of induced pluripotent stem cells (iPSCs).1
379958672024RET Signaling Persists in the Adult Intestine and Stimulates Motility by Limiting PYY Release From Enteroendocrine Cells.0
380611152024Comprehensive molecular analysis identifies RET alterations association with response of ICIs in multi-immunotherapy cohorts.1
384659992024Accelerated MEN2A in homozygous RET carriers in the context of consanguinity.0
384930962024Aberrant SOX10 and RET expressions in patients with Hirschsprung disease.0
385762882024Correlation Between the Clinicopathological Features of Papillary Thyroid Carcinoma Complicated with Hashimoto's Thyroiditis, BRAF V600E Gene Mutation, and RET Gene Rearrangement.0
385980202024BRAF and RET polymorphism association with thyroid cancer risk, a preliminary study from Khyber Pakhtunkhwa population.0
386238032024Non-syndromic Hirschsprung's disease as a result of a RET gene variant.0
387346212024Next-generation sequencing identified that RET variation associates with lymph node metastasis and the immune microenvironment in thyroid papillary carcinoma.0
388052862024CCDC6-RET fusion protein regulates Ras/MAPK signaling through the fusion- GRB2-SHC1 signal niche.0
379217252024Impact of the overexpression of the tyrosine kinase receptor RET in the hematopoietic potential of induced pluripotent stem cells (iPSCs).1
379958672024RET Signaling Persists in the Adult Intestine and Stimulates Motility by Limiting PYY Release From Enteroendocrine Cells.0
380611152024Comprehensive molecular analysis identifies RET alterations association with response of ICIs in multi-immunotherapy cohorts.1
384659992024Accelerated MEN2A in homozygous RET carriers in the context of consanguinity.0
384930962024Aberrant SOX10 and RET expressions in patients with Hirschsprung disease.0

Citation

Jean Loup Huret ; Sylvie Yau Chun Wan-Senon

RET (REarranged during Transfection)

Atlas Genet Cytogenet Oncol Haematol. 2020-06-01

Online version: http://atlasgeneticsoncology.org/gene/76/js/css/meetings/

Historical Card

2003-10-01 RET (REarranged during Transfection) by  Patricia Niccoli-Sire 

Service dEndocrinologie, Diaböte et Maladies Métaboliques, Hôpital de la Timone, 254, rue St Pierre, 13385 Marseille cedex 05, France