KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog)
| Written | 1998-09 | Lidia Larizza, Alessandro Beghini |
| Medical Genetics, San Paolo School of Medicine, University of Milan Via A. di Rudini, 8, 20142 Milano, Italy | ||
| Updated | 2000-06 | Lidia Larizza, Alessandro Beghini |
| Medical Genetics, San Paolo School of Medicine, University of Milan Via A. di Rudini, 8, 20142 Milano, Italy | ||
| Updated | 2015-11 | Lars Rönnstrand, Johan Lennartsson |
| Division of Translational Cancer Research and, Lund Stem Cell Center, Lund University, Lund, Sweden. lars.ronnstrand@med.lu.se, Ludwig Institute for Cancer Research, Uppsala, Sweden |
(Note : for Links provided by Atlas : click)
1. Identity
| Alias_names | General Information |
| piebald trait | |
| v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog | |
| Alias_symbol (synonym) | CD117 |
| SCFR | |
| C-Kit | |
| Other alias | SCFR (Stem Cell Factor Receptor) |
| HGNC (Hugo) | KIT |
| LocusID (NCBI) | 3815 |
| Atlas_Id | 127 |
| Location | 4q12 [Link to chromosome band 4q12] |
| Location_base_pair | Starts at 54657928 and ends at 54740715 bp from pter ( according to hg19-Feb_2009) [Mapping KIT.png] |
| Local_order | centromere-PDGFRA -KIT-KDR-telomer |
 | |
| KIT (4q12) - Courtesy Mariano Rocchi | |
| Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
| CNTRL (9q33.2) / KIT (4q12) | KIT (4q12) / MAATS1 (3q13.33) | KIT (4q12) / UGT2B7 (4q13.2) | |
| RCOR1 (14q32.31) / KIT (4q12) |
2. DNA/RNA
| Description | The KIT gene located on human chromsome 4q11 and contains 21 exons. Exon1 encodes the initation codon, exon 2-9 encodes the extracellular domain, exon 10 the transmembrane region and exons 11-21 the intracellular part. |
| Transcription | The 5.23 kb mRNA is alternatively spliced into two isoforms differing in the presence or absence of exon 9. This splicing gives rise to KIT variants that differ by the presence or absence of the amino acid sequence GNNK (denoted KIT and KITA, respectively). In addition there is alterative splicing occurring in humans, but not in mice, giving rise of isoforms that differ by the presence or absence of a serine residue in the kinase insert region. In postmeiotic germ cells a shorter KIT transcript is expressed that gives rise to a truncated version of KIT (tr-KIT) containing part of the kinase domain and the C-terminal tail. |
3. Protein
| Description | 976 aa; 145 kDa; type III receptor tyrosine kinase; glycoprotein; contains an extracellular domains with 5 Ig-like loops, a highly hydrophobic transmembrane domain (23 aa), and an intracellular domain with tyrosine kinase activity split by a kinase insert (KI) in an ATP-binding region and in the phosphotransferase domain. Tr-KIT does not contain the whole kinase domain and is therefore kinase inactive. |
| Expression | Hematopoietic stem cells, mast cells, melanocytes, germ-cell lineages and ICCs (Interstitial cells of Cajal). Expression pattern in the mouse suggest that KIT may play a role in tissues such as nervous system, placenta, heart, lung and midgestational kidneys. |
| Localisation | Plasma membrane. The truncated tr-KIT lacks the transmembrane domain and is hence not present at the plasma membrane. |
| Function | KIT is a cell surface receptor with tyrosine kinase activity; binding of ligand KITLG (also denoted MGF or SCF) induces receptor dimerization, autophosphorylation and signal transduction via molecules containing SH2- domains. KIT signaling leads to cell proliferation, survival, migration and differentiation. |
| Homology | with CSF-1R, PDGFRB, PDGFRA, and FLT3. |
 | |
| Loss-of-function mutations. | |
 | |
| Gain-of-function mutations. | |
4. Mutations
| Note | See figures Loss-of-function mutations and Gain-of-function mutations. |
5. Implicated in
| Note | |
| Entity | Piebaldism |
| Disease | Autosomal dominant disorder of pigmentation; loss of function abnormalities of the KIT gene have been demonstrated in 59% of the typical patients. |
| Entity | Familial Gastrointestinal Stromal Tumors and sporadic gastrointestinal stromal tumors (GISTs) |
| Disease | GISTs are the most common mesenchymal tumors in the human digestive tract; they originate from KIT-expressing cells (ICCs). All GISTs express KIT which is frequently (80-85% of the cases) mutated in exon 11 encoding the juxtamembrane domain. However, also mutations in exon 9 (encoding the extracellular region) and 17 (encoding a region around the activation loop in the kinase domain) have been found. Most GIST cells produce SCF thus establishing autocrine stimulation. |
| Entity | Systemic Mast Cell Disease (SMCD) |
| Disease | Mast cell hyperplasia in the bone marrow, liver, spleen, lymph nodes, gastrointestinal tract and skin; gain of function mutations are detected in most patients. About 90% of patients with systemic mastocytosis have mutation in exon 17 in KIT, often Asp-816 is replaced with Val. In children with systemic mastocytosis the frequency of KIT mutations in exon 17 is lower (about 40%), but mutations in other KIT regions are found in 40% of the children, for example mutation in exon 8 and 9 (encoding Ig-like domain 5 in the extracellular region of KIT). |
| Prognosis | The prognosis depends on the four clinical entities recognized: indolent form, form associated with hematologic disorder, aggressive SMCD and mast cell leukemia; leukemic transformation with mast cell involvement is characterized by rapid progression of disease with a survival time less than 1 year |
| Oncogenesis | clinical features of malignant hematopoietic cell growth are influenced by the time, the location of c-kit mutative events, and the number of associated lesions. |
| Entity | Small Cell Lung cancer (SCLC) |
| Disease | KIT overexpression is found in 70% of SCLC patients. Co-expression ofKIT and SCF has been found to create an autocrine loop. The prognostic value of KIT expression is not clear. |
| Entity | Testicular Carcinoma |
| Disease | Activating mutations in KIT exon 17 is found in about 25% of seminomas. Often Asp-816 is replaced with a Val or His residue. |
| Entity | Melanoma |
| Disease | KIT is important for the development of melanocytes. The about 80% of melanomas contain BRAF mutations, but a subset contain activating KITmutations. Interestingly in acral melanomas (affecting foot soles or palms) there is a higher frequency of tumors with activating KIT mutations (20-25% of cases). Examples of KIT mutations found in melanoma are L576P (in exon 11) and K642E (in exon 13). Mutation in position 816 (in exon 17) has also been observed but is not so frequent occurring. |
| Entity | Acute Myeloid Leukemia |
| Disease | KIT expression can be found in about 85% of AML cells. KIT activation can occur by different mechanisms: 1) co-expression of SCF causing an autocrine loop 2) activating mutations in exon 17 affecting Asp-816 or Asn-822. Interestingly, KIT mutations occurs primarily in a subset of leukemias containing inv(16) or t(8;21), so-called core factor binding AML. Apart from exon 17 mutations, also internal tandem duplications in exon 11 have been described. |
| Prognosis | Presence of D816V mutation in KIT is a poor prognostic factor. |
6. To be noted
| Loss of expression of KIT appears to be associated with progression of some tumors (melanoma) and autocrine/paracrine stimulation of the KIT/KITLG system may participate in human solid tumors such as lung, breast, testicular and gynecological malignancies. |
7. Bibliography
| Sequence analysis of two genomic regions containing the KIT and the FMS receptor tyrosine kinase genes. |
| Andre C, Hampe A, Lachaume P, Martin E, Wang XP, Manus V, Hu WX, Galibert F |
| Genomics. 1997 ; 39 (2) : 216-226. |
| PMID 9027509 |
| C-kit mutations in core binding factor leukemias. |
| Beghini A, Peterlongo P, Ripamonti CB, Larizza L, Cairoli R, Morra E, Mecucci C |
| Blood. 2000 ; 95 (2) : 726-727. |
| PMID 10660321 |
| Somatic activation of KIT in distinct subtypes of melanoma. |
| Curtin JA, Busam K, Pinkel D, Bastian BC |
| J Clin Oncol. 2006; 24:43406. |
| PMID 16908931 |
| Novel mutations and deletions of the KIT (steel factor receptor) gene in human piebaldism. |
| Ezoe K, Holmes SA, Ho L, Bennett CP, Bolognia JL, Brueton L, Burn J, Falabella R, Gatto EM, Ishii N |
| American journal of human genetics. 1995 ; 56 (1) : 58-66. |
| PMID 7529964 |
| c-kit proto-oncogene exon 8 in-frame deletion plus insertion mutations in acute myeloid leukaemia. |
| Gari M, Goodeve A, Wilson G, Winship P, Langabeer S, Linch D, Vandenberghe E, Peake I, Reilly J |
| British journal of haematology. 1999 ; 105 (4) : 894-900. |
| PMID 10554798 |
| Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. |
| Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Kanakura Y, Shinomura Y, Kitamura Y |
| Science (New York, N.Y.). 1998 ; 279 (5350) : 577-580. |
| PMID 9438854 |
| Stem cell factor receptor/c-Kit: from basic science to clinical implications . |
| Lennartsson J and Rönnstrand L |
| Physiol Rev. 2012; 92(4):1619-49 |
| PMID 23073628 |
| Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. |
| Longley BJ Jr, Metcalfe DD, Tharp M, Wang X, Tyrrell L, Lu SZ, Heitjan D, Ma Y |
| Proceedings of the National Academy of Sciences of the United States of America. 1999 ; 96 (4) : 1609-1614. |
| PMID 9990072 |
| Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. |
| Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG, Duffy T, Jacobs P, Tang LH, Modlin I |
| Nature genetics. 1996 ; 12 (3) : 312-314. |
| PMID 8589724 |
| KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors. |
| Lux ML, Rubin BP, Biase TL, Chen CJ, Maclure T, Demetri G, Xiao S, Singer S, Fletcher CD, Fletcher JA |
| The American journal of pathology. 2000 ; 156 (3) : 791-795. |
| PMID 10702394 |
| C-kit gene abnormalities in gastrointestinal stromal tumors (tumors of interstitial cells of Cajal. |
| Sakurai S, Fukasawa T, Chong JM, Tanaka A, Fukayama M |
| Japanese journal of cancer research : Gann. 1999 ; 90 (12) : 1321-1328. |
| PMID 10665649 |
| Activating c-kit gene mutations in human germ cell tumors. |
| Tian Q, Frierson HF Jr, Krystal GW, Moskaluk CA |
| The American journal of pathology. 1999 ; 154 (6) : 1643-1647. |
| PMID 10362788 |
| Cloning and structural analysis of the human c-kit gene. |
| Vandenbark GR, deCastro CM, Taylor H, Dew-Knight S, Kaufman RE |
| Oncogene. 1992 ; 7 (7) : 1259-1266. |
| PMID 1377810 |
| Human malignant melanoma: detection of BRAF- and c-kit-activating mutations by high-resolution amplicon melting analysis. |
| Willmore-Payne C, Holden JA, Tripp S, Layfield LJ |
| Human Pathol 2005; 36(5):486-93. |
| PMID 15948115 |
| Targeting KIT in melanoma: A paradigm of molecular medicine and targeted therapeutics. Review |
| Woodman SE and Davies MA |
| Biochem Pharmacol 2010; 80(5):568-74. |
| PMID 20457136 |
8. Citation
| This paper should be referenced as such : |
| Lars Rnnstrand, Johan Lennartsson |
| KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) |
| Atlas Genet Cytogenet Oncol Haematol. 2016;20(8):441-444. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://atlasgeneticsoncology.usal.es/classic/Genes/KITID127.html |
| History of this paper: |
| Larizza, L ; Beghini, A. KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog). Atlas Genet Cytogenet Oncol Haematol. 1999;3(1):1-3. |
| http://documents.irevues.inist.fr/bitstream/handle/2042/37473/09-1998-KITID127.pdf |
| Larizza, L ; Beghini, A. KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog). Atlas Genet Cytogenet Oncol Haematol. 2000;4(3):96-98. |
| http://documents.irevues.inist.fr/bitstream/handle/2042/37632/06-2000-KITID127.pdf |
9. Other Leukemias implicated (Data extracted from papers in the Atlas) [ 2 ]
|
Systemic mast cell disease (SMCD)
t(4;9)(q12;q33) CNTRL/KIT |
| Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 3 ] |
|
Head and Neck: Primary oral mucosal melanoma
t(4;4)(q12;q13) KIT/UGT2B7 t(4;14)(q12;q32) RCOR1/KIT |
| Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 2 ] |
| Familial /sporadic gastrointestinal stromal tumors (GISTs) Piebaldism |
10. External links
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Thu Jan 17 18:58:56 CET 2019 |
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