mercredi 6 juin 2012

Mutated genes in cancer (74) – KIT


In databases:

● Entrez ( 3815 or KIT
● Ensembl ( ENSG00000157404
● UniProt ( P10721
● GeneCards ( KIT
● HGNC ( 6342 or KIT
● Enzyme Number (IUBMB): EC 2.7.10, EC

Gene locus:


Protein name:

v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog

Protein Size:

976 amino acids; about 110 kDa


KIT encodes the receptor for stem cell factor (SCF). It is a tyrosine-protein kinase activity. Binding of the ligands leads to the autophosphorylation of KIT and its association with substrates such as phosphatidylinositol 3-kinase (Pi3K).

Cancer-related alterations:

Germinal KIT mutations are a cause of familial GISTs. GISTs are the most common mesenchymal tumors in the human digestive tract; they originate from KIT-expressing cells and often have activating KIT mutations clustered in the juxtamembrane domain. GISTs may also be caused by somatic KIT alterations. Mutations in PDGFRA may also induce GISTs.

Somatic KIT mutations are observed in many tumor types. These include tumors of soft tissue, haematopoietic and lymphoid tissue, genital tract, testis, salivary glands… KIT mutations are notably involved in systemic mast cell disease (SMCD), which is characterized by cell hyperplasia in the bone marrow, liver, spleen, lymph nodes, gastrointestinal tract and skin; gain of function mutations are detected in most patients.

KIT mutations are also seen in core binding factor (CBF) leukemias, which are characterized by disruption and loss of CBFa2/AML1 - CBFb/PEBP2b function.

Substitutions account for about one-half of somatic mutations. There is a mutation hot spot corresponding to amino acid 816 and around this site. Most complex mutations are seen in regions corresponding to amino acids 417-419 and 547-571.


Imatinib and sunitinib, both tyrosine kinase inhibitors directed to KIT, were approved for first- and second-line treatment of metastatic and unresectable GISTs.
Downsizing TKI is recommended for patients with bulky tumors with invasion of adjacent organs. Sunitinib can be used for patients in case of imatinib resistance (e.g., wild-type GISTs), underlining the importance of mutational analysis for optimal surgical planning.

References (open access):

Gastrointestinal stromal tumors: molecular mechanisms and targeted therapies. Downs-Kelly E, Rubin BP. Patholog Res Int. 2011 Apr 14;2011:708596.

ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours. Chi P, Chen Y, Zhang L, Guo X, Wongvipat J, Shamu T, Fletcher JA, Dewell S, Maki RG, Zheng D, Antonescu CR, Allis CD, Sawyers CL. Nature. 2010 Oct 14;467(7317):849-53.

Mutations in the c-Kit gene disrupt mitogen-activated protein kinase signaling during tumor development in adenoid cystic carcinoma of the salivary glands. Tetsu O, Phuchareon J, Chou A, Cox DP, Eisele DW, Jordan RC. Neoplasia. 2010 Sep;12(9):708-17.

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