RET (REarranged during Transfection)
2020-06-01 Jean Loup Huret , Sylvie Yau Chun Wan-Senon AffiliationIdentity
HGNC
LOCATION
10q11.21
LOCUSID
ALIAS
CDHF12,CDHR16,HSCR1,MEN2A,MEN2B,MTC1,PTC,RET-ELE1
FUSION GENES
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
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.
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.
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.
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:
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).
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).
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).
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).
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).
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
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 Gene | Chrom. | Location: band (bp) | Translocation / fusion gene | Disease |
| TRIM33 | 1 | 1p13.2 (114392777) | t(1;10)(p13;q11) TRIM33/RET | Lung: non-small cell lung carcinoma |
| Thyroid: papillary thyroid carcinoma | ||||
| RASAL2 | 1q25.2 (178093729) | t(1;10)(q25;q11) RASAL2/RET | Soft tissue sarcoma | |
| EML4 | 2 | 2p21 (42169338)) | t(2;10)(p21;q11) EML4/RET | Lung: non-small cell lung carcinoma |
| EML6 | 2p16.1 (54725012 | t(2;10)(p16;q11) EML6/RET | Lung: non-small cell lung carcinoma | |
| TFG | 3 | 3q12.2 (100709331) | t(3;10)(q12;q11) TFG/RET | Soft tissues: spindle cell tumors |
| TBL1XR1 | 3q26.32 (177019355) | t(3;10)(q26;q11) TBL1XR1/RET | Thyroid: papillary thyroid carcinoma | |
| EPHA5 | 4 | 4q13.1 (65319563) | t(4;10)(q13;q11) APHA5/RET | Lung: non-small cell lung carcinoma |
| SQSTM1 | 5 | 5q35.3 (179820842) | t(5;10)(q35;q11) SQSTM1/RET | Thyroid: papillary thyroid carcinoma |
| KIF13A | 6 | 6p22.3 (17763693) | t(6;10)(p22;q11) KIF13A/RET | Lung: adenocarcinoma |
| TRIM27 | 6p22.1 (28903002) | t(6;10)(p22;q11) TRIM27/RET | Salivary glands: intraductal carcinoma | |
| Thyroid: papillary thyroid carcinoma | ||||
| Neuro-endocrine tumor: multiple endocrine neoplasia | ||||
| TBC1D32 | 6q22.31 (121079494) | t(6;10)(q22;q11) TBC1D32/RET | Lung: adenocarcinoma | |
| PTPRK | 6q22.33 (127968779) | t(6;10)(q22;q11) PTPRK/RET | Lung: non-small cell lung carcinoma | |
| FGFR1OP | 6q27 (166,999,317) | t(6;10)(q27;q11) FGFR1OP/RET | Chronic myeloproliferative neoplasm | |
| CLIP2 | 7 | 7q11.23 (74289475) | t(7;10)(q11;q11) CLIP2/RET | Soft tissues: spindle mesenchymal neoplasm |
| CUX1 | 7q22.1 (101817602) | t(7;10)(q22,q11) CUX1/RET | Lung: non-small cell lung carcinoma | |
| TRIM24 | 7q33 (138460334) | t(7;10)(q33;q11) TRIM24/RET | Lung: non-small cell lung carcinoma | |
| Thyroid: papillary thyroid carcinoma | ||||
| TAS2R38 | 7q34 (141972631) | t(7;10)(q34;q11) TAS2R38/RET | Thyroid: papillary thyroid carcinoma | |
| PCM1 | 8 | 8p22 (17922857) | t(8;10)(p22;q11) PCM1/RET | Lung: non-small cell lung carcinoma |
| Thyroid: papillary thyroid carcinoma | ||||
| RBPMS | 8p12 (30384501) | t(8;10)(p12;q11) RBPMS/RET | Lung: non-small cell lung carcinoma | |
| HOOK3 | 8p11.21 (42896890) | t(8;10)(p11;q11) HOOK3/RET | Thyroid: papillary thyroid carcinoma | |
| FKBP15 | 9 | 9q32 (113165520) | t(9;10)(q32;q11) FKBP15/RET | Thyroid: papillary thyroid carcinoma |
| PRKCQ | 10 | 10p15.1 (6427143) | t(10;10)(p15;q11) PRKCQ/RET | Lung: non-small cell lung carcinoma |
| TAF3 | 10p14 (7818504) | t(10;10)(p14;q11) TAF3/RET | Thyroid: papillary thyroid carcinoma | |
| CCDC3 | 10p13 (12896625) | t(10;10)(p13;q11) CCDC3/RET | Lung: non-small cell lung carcinoma | |
| PRPF18 | 10p13 (13586939) | t(10;10)(p13;q11) PRPF18/RET | Lung: non-small cell lung carcinoma | |
| FRMD4A | 10p13 (13643706) | t(10;10)(p13;q11) FRMD4A/RET | Lung: non-small cell lung carcinoma | |
| KIAA1217 | 10p12.2 (24208791) | t(10;10)(p12;q11) KIAA1217/RET | Lung: adenocarcinoma | |
| Soft tissues: spindle mesenchymal neoplasm | ||||
| ANKRD26 | 10p12.1 (27004116) | t(10;10)(p12,q11) ANKRD26/RET | Thyroid: papillary thyroid carcinoma | |
| ACBD5 | 10p12.1 (27195214) | t(10;10)(p12;q11) ACBD5/RET | Thyroid: papillary thyroid carcinoma | |
| WAC | 10p12.1 (28533492) | t(10;10)(p12;q11) WAC/RET | Lung: non-small cell lung carcinoma | |
| ARHGAP12 | 10p11.22 (31805398) | t(10;10)(p11;q11) ARHGAP12/RET | Lung: non-small cell lung carcinoma | |
| KIF5B | 10p11.22 (32009010 ) | t(10;10)(p11;q11) KIF5B/RET | Lung: non-small cell lung carcinoma | |
| Skin: melanomas/Spitz tumors | ||||
| Thyroid: papillary thyroid carcinoma | ||||
| PARD3 | 10p11.22 (34109560) | t(10;10)(p11;q11) PARD3/RET | Lung: non-small cell lung carcinoma | |
| CCNYL2 | 10q11.21 (42408174) | CCNYL2/RET (10q11) | Lung: non-small cell lung carcinoma | |
| RASGEF1A | 10q11.21 (43194533) | RASGEF1A/RET (10q11) | Breast cancer | |
| RASSF4 | 10q11.21 (44959771) | RASSF4/RET (10q11) | Lung: non-small cell lung carcinoma | |
| NCOA4 | 10q11.23 (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 | ||||
| PRKG1 | 10q11.23 (51074474) | PRKG1/RET (10q11) | Lung: non-small cell lung carcinoma | |
| ANK3 | 10q21.2 (60026298) | t(10;10)(q11;q21) ANK3/RET | Thyroid: papillary thyroid carcinoma | |
| SLC16A9 | 10q21.2 (59650764) | t(10;10))(q11;q21) SLC16A9/RET | Thyroid: papillary thyroid carcinoma | |
| CCDC6 | 10q21.2 (59788748) | t(10;10)(q11;q21) CCDC6/RET | Colorectal cancer | |
| Lung: non-small cell lung carcinoma | ||||
| Thyroid: papillary thyroid carcinoma | ||||
| CTNNA3 | 10q21.3 (65912518) | t(10;10)(q11;q21) CTNNA3/RET | Lung: non-small cell lung carcinoma | |
| SIRT1 | 10q21.3 (67884669) | t(10;10)(q11;q21) SIRT1/RET | Lung: non-small cell lung carcinoma | |
| RUFY2 | 10q21.3 (68343518) | t(10;10)(q11;q21) RUFY2/RET | Lung: non-small cell lung carcinoma | |
| Thyroid: papillary thyroid carcinoma | ||||
| DYDC1 | 10q23.1 (80336106) | t(10;10)(q11;q23) DYDC1/RET | Lung: non-small cell lung carcinoma | |
| SORBS1 | 10q24 (110005804) | t(10;10)(q11;q24) SORBS1/RET | Lung: non-small cell lung carcinoma | |
| ADD3 | 10q25.1 (114161608) | t(10;10)(q11;q25) ADD3/RET | Lung: non-small cell lung carcinoma | |
| CCDC186 | 10q25.3 (114294824) | t(10;10)(q11;q25) CCDC186/RET | Lung: non-small cell lung carcinoma | |
| AFAP1L2 | 10q25.3 (126905409) | t(10;10)(q11;q25) AFAP1L2/RET | Thyroid: papillary thyroid carcinoma | |
| DOCK1 | 10q26.2 (126905409) | t(10;10)(q11;q26) DOCK1/RET | Lung: non-small cell lung carcinoma | |
| CLRN3 | 10q26.2 (127877841) | t(10;10)(q11;q26) CLRN3/RET | Thyroid: papillary thyroid carcinoma | |
| PPFIBP2 | 11 | 11p15.4 (7513765) | t(10;11)(q11;p15) PPFIBP2/RET | Thyroid: papillary thyroid carcinoma |
| PICALM | 11q14.2 (85957171) | t(10;11)(q11;q14) PICALM/RET | Lung: non-small cell lung carcinoma | |
| ETV6 | 12 | 12p13.2 (11649854) | t(10;12)(q11;p13) ETV6/RET | Salivary glands: mammary analog secretory carcinoma |
| ERC1 | 12q13.33 (991208 ) | t(10;12)(q11;q13) ERC1/RET | Breast cancer | |
| Lung: non-small cell lung carcinoma | ||||
| Thyroid: papillary thyroid carcinoma | ||||
| ANKS1B | 12q23.1 (98743974) | t(10;12)(q11;q23) ANKS1B/RET | Lung: non-small cell lung carcinoma | |
| CLIP1 | 12q24.31 (122271434) | t(10;12)(q11;q24) CLIP1/RET | Lung: non-small cell lung carcinoma | |
| TSSK4 | 14 | 14q12 (24205720) | t(10;14)(q11;q12) TSSK4/RET | Lung: non-small cell lung carcinoma |
| KTN1 | 14q22.3 (55580207) | t(10;14)(q11;q22) KTN1/RET | Thyroid: papillary thyroid carcinoma | |
| CCDC88C | 14q32.11 (91271323) | t(10;14)(q11;q32) CCDC88C/RET | Lung: non-small cell lung carcinoma | |
| GOLGA5 | 14q32.12 (92794231) | t(10;14)(q11;q32) GOLGA5/RET | Skin: melanomas/Spitz tumors | |
| Thyroid: papillary thyroid carcinoma | ||||
| MYO5C | 15 | 15q21.2 (52192318) | t(10;15)(q11;q21) MYO5C/RET | Lung: non-small cell lung carcinoma |
| AKAP13 | 15q25.3 (85380616) | t(10;15)(q11;q25) AKAP13/RET | Thyroid: papillary thyroid carcinoma | |
| MYH10 | 17 | 17p13.1 (8474205) | t(10;17)(q11;p13) MYH10/RET | Soft tissues: Infantile myofibromatosis |
| Soft tissues: spindle mesenchymal neoplasm | ||||
| MYH13 | 17p13.1 (10300866) | t(10;17)(q11;p13) MYH13/RET | Thyroid: papillary thyroid carcinoma | |
| MPRIP | 17p11.2 (17042760) | t(10;17)(q11;p11) MPRIP/RET | Lung: non-small cell lung carcinoma | |
| PRKAR1A | 17q24.2 (68512379) | t(10;17)(q11;q24) PRKAR1A/RET | Lung: non-small cell lung carcinoma | |
| Neuro-endocrine tumor | ||||
| RELCH (KIAA1468) | 18 | 18q21.33 (62187291) | t(10;18)(q11;q21) KIAA1468/RET | Lung: adenocarcinoma |
| Lung: non-small cell lung carcinoma | ||||
| Thyroid: papillary thyroid carcinoma | ||||
| LSM14A | 19 | 19q13.11 (34172447) | t(10;19)(q11;q13) LSM14A/RET | Lung: adenocarcinoma |
| RRBP1 | 20 | 20p12.1 (17613678) | t(10;20)(q11;p12) RRBP1/RET | Colorectal cancer |
| BCR | 22 | 22q11.23 (23180365) | t(10;22)(q11;q11) BCR/RET | Chronic myeloproliferative neoplasm |
| SPECC1L | 22q11.23 (24270817) | t(10;22)(q11;q11) SPECC1L/RET | Thyroid: papillary thyroid carcinoma | |
| TIMP3 | 22q12.3 (32800816) | t(10;22)(q11 ;q12) TIMP3/RET | Soft tissues: Inflammatory myofibroblastic tumor |
Implicated in
Entity name
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
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.
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).
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)
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.
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).
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.
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
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).
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).
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).
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).
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
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
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
TABLE 2: Breakpoints according to Cosmic
| Hybrid Gene | Partner Gene | Last Exon | Breakpoint | RET | RET First Exon | Breakpoint | Tissue |
| TRIM33/RET | 5 TRIM33 | 16 | 1_2976 | 3 RET | 12 | 2369_5659 | Thyroid (0.7%) |
| TRIM27/RET | 5 TRIM27 | 3 | 1_1104+6742 | 3 RET | 12 | 2369-1668_5659 | Thyroid (1.4%) |
| TRIM24/RET | 5 TRIM24 | 9 | 1_1745 | 3 RET | 12 | 2369_5659 | Thyroid (0.7%) |
| PCM1/RET | 5 PCM1 | 29 | 1_5266 | 3 RET | 12 | 2369_5659 | Thyroid (1.8%) |
| HOOK3/RET | 5 HOOK3 | 11 | 1_1322 | 3 RET | 12 | 2369_5659 | Thyroid (1.8%) |
| KIF5B/RET | 5 KIF5B | 15 | 1_2183 | 3 RET | 12 | 2369_5659 | |
| 5 KIF5B | 16 | 1_2372 | 3 RET | 12 | 2369_5659 | Skin 2.6%; Lung (1.5%) | |
| NCOA4/RET | 5 NCOA4 | 8 | 1_907 | 3 RET | 12 | 2369_5659 | Thyroid (8%), Lung, Soft tissue |
| CCDC6/RET | 5 CCDC6 | 1 | 1_535 | 3 RET | 12 | 2369_5659 | Thyroid (12.7%;) Lung 50.5% |
| ERC1/RET | 5 ERC1 | 11 | 1_2338 | 3 RET | 12 | 2369_5659 | Thyroid (1%) |
| KTN1/RET | 5 KTN1 | 29 | 1_2960 | 3 RET | 12 | 2369_5659 | Thyroid (1.4%) |
| GOLGA5/RET | 5 GOLGA5 | 7 | 1_1747 | 3 RET | 12 | 2369_5659 | Skin (2.6%); Thyroid (0.8%) |
| PRKAR1A/RET | 5 PRKAR1A | 7 | 1_825 | 3 RET | 12 | 2369_5659 | Thyroid (2.7%) |
| RELCH/RET | 5 RELCH | 10 | 1_1852 | 3 RET | 12 | 2369_5659 | Lung (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 ID | Last Year | Title | Authors |
|---|---|---|---|
| 30310176 | 2019 | Aberrant receptor tyrosine kinase signaling in lipofibromatosis: a clinicopathological and molecular genetic study of 20 cases. | Al-Ibraheemi A et al |
| 12640453 | 2003 | Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. | Amiel J et al |
| 11445581 | 2001 | Molecular modeling of the extracellular domain of the RET receptor tyrosine kinase reveals multiple cadherin-like domains and a calcium-binding site. | Anders J et al |
| 27935748 | 2017 | ATF4 Targets RET for Degradation and Is a Candidate Tumor Suppressor Gene in Medullary Thyroid Cancer. | Bagheri-Yarmand R et al |
| 22513837 | 2012 | RET fusion genes are associated with chronic myelomonocytic leukemia and enhance monocytic differentiation. | Ballerini P et al |
| 28490466 | 2017 | RET Signaling in Prostate Cancer. | Ban K et al |
| 22189301 | 2012 | The RET G691S polymorphism is a germline variant in desmoplastic malignant melanoma. | Barr J et al |
| 31392261 | 2019 | Cryo-EM structure of the activated RET signaling complex reveals the importance of its cysteine-rich domain. | Bigalke JM et al |
| 8826440 | 1996 | Congenital central hypoventilation syndrome: mutation analysis of the receptor tyrosine kinase RET. | Bolk S et al |
| 24315414 | 2014 | Functional characterization of a novel FGFR1OP-RET rearrangement in hematopoietic malignancies. | Bossi D et al |
| 23528997 | 2013 | The developmental etiology and pathogenesis of Hirschsprung disease. | Butler Tjaden NE et al |
| 23378251 | 2013 | KIF5B-RET fusions in Chinese patients with non-small cell lung cancer. | Cai W et al |
| 24548782 | 2014 | The prognostic role of intragenic copy number breakpoints and identification of novel fusion genes in paediatric high grade glioma. | Carvalho D et al |
| 28931560 | 2018 | RET-mediated modulation of tumor microenvironment and immune response in multiple endocrine neoplasia type 2 (MEN2). | Castellone MD et al |
| 22312249 | 2012 | Molecular basis of medullary thyroid carcinoma: the role of RET polymorphisms. | Ceolin L et al |
| 31917155 | 2020 | Uterine inflammatory myofibroblastic tumors in pregnant women with and without involvement of the placenta: a study of 6 cases with identification of a novel TIMP3-RET fusion. | Cheek EH et al |
| 31605946 | 2019 | Genetic Landscape of Somatic Mutations in a Large Cohort of Sporadic Medullary Thyroid Carcinomas Studied by Next-Generation Targeted Sequencing. | Ciampi R et al |
| 31994201 | 2020 | Recurrent RET gene fusions in paediatric spindle mesenchymal neoplasms. | Davis JL et al |
| 24022366 | 2014 | To bud or not to bud: the RET perspective in CAKUT. | Davis TK et al |
| 29617662 | 2018 | Driver Fusions and Their Implications in the Development and Treatment of Human Cancers. | Gao Q et al |
| 9858145 | 1998 | Differential expression of the RET gene in human acute myeloid leukemia. | Gattei V et al |
| 23868506 | 2013 | Ret inhibition decreases growth and metastatic potential of estrogen receptor positive breast cancer cells. | Gattelli A et al |
| 28447912 | 2017 | Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry. | Gautschi O et al |
| 25242331 | 2014 | RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association. | Goodman KM et al |
| 32293499 | 2020 | Oncogenic and drug-sensitive RET mutations in human epithelial ovarian cancer. | Guan L et al |
| 30130630 | 2019 | Novel gene fusions in secretory carcinoma of the salivary glands: enlarging the ETV6 family. | Guilmette J et al |
| 26686064 | 2016 | Vandetanib as a potential new treatment for estrogen receptor-negative breast cancers. | Hatem R et al |
| 29413423 | 2018 | Genomic Landscape of Pheochromocytoma and Paraganglioma. | Jochmanova I et al |
| 2588107 | 1989 | Difficulties of parathyroidectomy after previous thyroidectomy. | Kadowaki MH et al |
| 27683183 | 2017 | RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients. | Kato S et al |
| 28512242 | 2017 | A Systematic Analysis of Oncogenic Gene Fusions in Primary Colon Cancer. | Kloosterman WP et al |
| 31711124 | 2020 | REToma: a cancer subtype with a shared driver oncogene. | Kohno T et al |
| 16029119 | 2005 | RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. | Kouvaraki MA et al |
| 24699901 | 2014 | RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma. | Krampitz GW et al |
| 26078337 | 2015 | Identification and characterization of RET fusions in advanced colorectal cancer. | Le Rolle AF et al |
| 31715421 | 2019 | RET fusions in solid tumors. | Li AY et al |
| 22327622 | 2012 | Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. | Lipson D et al |
| 31411754 | 2020 | Novel TFG-RET fusion in a spindle cell tumour with S100 and CD34 coexpresssion. | Loong S et al |
| 31983649 | 2020 | [New mutations associated with Hirschsprung disease]. | Lorente-Ros M et al |
| 29665843 | 2018 | Next-generation sequencing analysis of receptor-type tyrosine kinase genes in surgically resected colon cancer: identification of gain-of-function mutations in the RET proto-oncogene. | Mendes Oliveira D et al |
| 30938880 | 2019 | S100 and CD34 positive spindle cell tumor with prominent perivascular hyalinization and a novel NCOA4-RET fusion. | Michal M et al |
| 30666215 | 2018 | GDNF and the RET Receptor in Cancer: New Insights and Therapeutic Potential. | Mulligan LM et al |
| 17270245 | 2007 | RET oncogene amplification in thyroid cancer: correlations with radiation-associated and high-grade malignancy. | Nakashima M et al |
| 19561646 | 2009 | Functional RET G691S polymorphism in cutaneous malignant melanoma. | Narita N et al |
| 31058838 | 2019 | Rearranged During Transfection Fusions in Non-Small Cell Lung Cancer. | O'Leary C et al |
| 24629636 | 2014 | ALK, ROS1 and RET fusions in 1139 lung adenocarcinomas: a comprehensive study of common and fusion pattern-specific clinicopathologic, histologic and cytologic features. | Pan Y et al |
| 30446652 | 2018 | RET rearrangements are actionable alterations in breast cancer. | Paratala BS et al |
| 29538669 | 2018 | RET fusions in a small subset of advanced colorectal cancers at risk of being neglected. | Pietrantonio F et al |
| 29175871 | 2018 | Structure and function of RET in multiple endocrine neoplasia type 2. | Plaza-Menacho I et al |
| 31300450 | 2019 | Analysis of Cell-Free DNA from 32,989 Advanced Cancers Reveals Novel Co-occurring Activating RET Alterations and Oncogenic Signaling Pathway Aberrations. | Rich TA et al |
| 28028925 | 2017 | A case of advanced infantile myofibromatosis harboring a novel MYH10-RET fusion. | Rosenzweig M et al |
| 25122419 | 2014 | RET mutations in neuroendocrine tumors: including small-cell lung cancer. | Rudin CM et al |
| 32326537 | 2020 | RET Gene Fusions in Malignancies of the Thyroid and Other Tissues. | Santoro M et al |
| 25330015 | 2014 | Association of RET genetic polymorphisms and haplotypes with papillary thyroid carcinoma in the Portuguese population: a case-control study. | Santos M et al |
| 16357163 | 2005 | The G691S RET polymorphism increases glial cell line-derived neurotrophic factor-induced pancreatic cancer cell invasion by amplifying mitogen-activated protein kinase signaling. | Sawai H et al |
| 31162284 | 2019 | NCOA4-RET and TRIM27-RET Are Characteristic Gene Fusions in Salivary Intraductal Carcinoma, Including Invasive and Metastatic Tumors: Is "Intraductal" Correct? | Skálová A et al |
| 29076873 | 2018 | Molecular Profiling of Mammary Analog Secretory Carcinoma Revealed a Subset of Tumors Harboring a Novel ETV6-RET Translocation: Report of 10 Cases. | Skalova A et al |
| 25204415 | 2014 | The landscape of kinase fusions in cancer. | Stransky N et al |
| 32094155 | 2020 | Advances in Targeting RET-Dependent Cancers. | Subbiah V et al |
| 32461304 | 2020 | Targeting RET Kinase in Neuroendocrine Prostate Cancer. | VanDeusen HR et al |
| 24445538 | 2014 | Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. | Wiesner T et al |
| 32062451 | 2020 | PTPRA Phosphatase Regulates GDNF-Dependent RET Signaling and Inhibits the RET Mutant MEN2A Oncogenic Potential. | Yadav L et al |
| 32220490 | 2020 | RASAL2-RET: a novel RET rearrangement in a patient with high-grade sarcoma of the chest. | Zhou Y et al |
Other Information
Locus ID:
NCBI: 5979
MIM: 164761
HGNC: 9967
Ensembl: ENSG00000165731
Variants:
dbSNP: 5979
ClinVar: 5979
TCGA: ENSG00000165731
COSMIC: RET
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
PharmGKB
| Entity ID | Name | Type | Evidence | Association | PK | PD | PMIDs |
|---|---|---|---|---|---|---|---|
| PA162372840 | sunitinib | Chemical | MultilinkAnnotation | associated | 19248971 | ||
| PA165906891 | cabozantinib | Chemical | LabelAnnotation | associated | |||
| PA166118341 | vandetanib | Chemical | LabelAnnotation, Literature, MultilinkAnnotation | associated | 24433361 | ||
| PA29444 | HRAS | Gene | Pathway | associated | 28362716 | ||
| PA30196 | KRAS | Gene | Pathway | associated | 28362716 | ||
| PA31768 | NRAS | Gene | Pathway | associated | 28362716 | ||
| PA31817 | NTRK1 | Gene | DataAnnotation | associated | |||
| PA445857 | Thyroid Neoplasms | Disease | Literature, MultilinkAnnotation | associated | 23788249 | ||
| PA446649 | Carcinoma, Medullary | Disease | DataAnnotation | associated | |||
| PA446772 | Multiple Endocrine Neoplasia Type 2a | Disease | DataAnnotation | associated | |||
| PA7000 | sorafenib | Chemical | Pathway | associated | 28362716 |
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 37921725 | 2024 | Impact of the overexpression of the tyrosine kinase receptor RET in the hematopoietic potential of induced pluripotent stem cells (iPSCs). | 1 |
| 37995867 | 2024 | RET Signaling Persists in the Adult Intestine and Stimulates Motility by Limiting PYY Release From Enteroendocrine Cells. | 0 |
| 38061115 | 2024 | Comprehensive molecular analysis identifies RET alterations association with response of ICIs in multi-immunotherapy cohorts. | 1 |
| 38465999 | 2024 | Accelerated MEN2A in homozygous RET carriers in the context of consanguinity. | 0 |
| 38493096 | 2024 | Aberrant SOX10 and RET expressions in patients with Hirschsprung disease. | 0 |
| 38576288 | 2024 | Correlation Between the Clinicopathological Features of Papillary Thyroid Carcinoma Complicated with Hashimoto's Thyroiditis, BRAF V600E Gene Mutation, and RET Gene Rearrangement. | 0 |
| 38598020 | 2024 | BRAF and RET polymorphism association with thyroid cancer risk, a preliminary study from Khyber Pakhtunkhwa population. | 0 |
| 38623803 | 2024 | Non-syndromic Hirschsprung's disease as a result of a RET gene variant. | 0 |
| 38734621 | 2024 | Next-generation sequencing identified that RET variation associates with lymph node metastasis and the immune microenvironment in thyroid papillary carcinoma. | 0 |
| 38805286 | 2024 | CCDC6-RET fusion protein regulates Ras/MAPK signaling through the fusion- GRB2-SHC1 signal niche. | 0 |
| 37921725 | 2024 | Impact of the overexpression of the tyrosine kinase receptor RET in the hematopoietic potential of induced pluripotent stem cells (iPSCs). | 1 |
| 37995867 | 2024 | RET Signaling Persists in the Adult Intestine and Stimulates Motility by Limiting PYY Release From Enteroendocrine Cells. | 0 |
| 38061115 | 2024 | Comprehensive molecular analysis identifies RET alterations association with response of ICIs in multi-immunotherapy cohorts. | 1 |
| 38465999 | 2024 | Accelerated MEN2A in homozygous RET carriers in the context of consanguinity. | 0 |
| 38493096 | 2024 | Aberrant 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/ret
Historical Card
2003-10-01 RET (REarranged during Transfection) by Patricia Niccoli-Sire Affiliation
Service dEndocrinologie, Diaböte et Maladies Métaboliques, Hôpital de la Timone, 254, rue St Pierre, 13385 Marseille cedex 05, France
