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).
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.
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.