Cancer, skin, bone, developmental, urological, and physiological disorders

Urticaria; Dysphagia; Alveolar capillary dysplasia (ACD); Juvenile xanthogranuloma; Kimura disease; Mixed gonadal dysgenesis; Chronic cystitis

Piebald Trait, Kit-Related is a rare genetic disease where there is the lack of pigment producing cells (melanocytes) in various areas around the skin and hair. Individuals suffering from Piebaldism (PBT) suffer from increased risks of skin cancer in the non-pigmented patches. In Piebald trait (PBT) a R796G mutation induced sensorineural deafness. PBT has correlated with the E583K, F584C, F584L, G601R, L565P, G664R, R791G, R796G, G812V, and T847P. Urticaria, often called hives, is characterized by an itchy skin rash. Dysphagia manifests with a difficulty of swallowing, and the disorder is related to muscular dystrophy and oculopharyngeal muscular dystrophy. Alveolar Capillary Dysplasia (ACD) is a rare respiratory and cardiovascular disease resulting in misalignment of pulmonary veins during development. Juvenile Xanthogranuloma is a rare form of non-langerhans cell histiocytes (tissue macrophages) and can result in anterior chamber anomaly, blindness, and conjunctivitis. Kimura Disease is an inflammation of sub-cutaneous nodes near the neck or head. It can also affect bone and kidney tissues. Mixed Gonadal Dysgenesis is a rare disorder that induces the asymetrical development of sex organs leading to mosaicism with regards to which sexual organs are prevalent. Chronic Cystitis is characterized by chronic inflammation of the bladder, but can also affect the prostate, testis, and pituitary gland.
 

Piebald Trait, Kit-Related; Piebaldism (PBT); Gastrointestinal stromal tumours (GANT, GIST); Sarcomas; Mastocytosis; Acute myeloid leukemias (AML); Seminoma; Germ Cell tumours (GCT); Leiomyosarcomas; Thymic carcinomas; Urticaria Pigmentosa; Dysgerminomas; Uterine carcinosarcomas; Uterine sarcomas; Myelofibrosis (MYELOF); Teratomas; Carney Triad; Gonadoblastomas; Desmoid tumours; Hypereosinophilic syndrome (HES); Gastrointestinal stromal tumours, Familial; Cutaneous mastocytosis (CM); Gastrointestinal stromal tumours, somatic; Systemic mastocytosis (SMCD); Adenoid cystic carcinomas; Small cell carcinomas; Core binding factor acute myeloid leukemias (AML) (CBF-AML); Mast-Cell leukemias; Indolent systemic mastocytosis (ISM); Thymic epithelial tumours; Aggressive systemic mastocytosis (ASM); Polymorphous low-grade adenocarcinomas (PLGA); Liposarcomas; Small cell neuroendocrine carcinomas; Cutaneous leiomyosarcomas; Mast cell neoplasms; Extragonadal seminoma; Thymic epithelial neoplasm (TEN); Juvenile nasopharyngeal angiofibroma (JNA); Male germ cell tumours; Sinonasal undifferentiated carcinomas (SNUC); Fibrosarcomas of bone; Dermatofibrosarcoma protuberans (DFSP); Perineuriomas; Adenosarcomas; Embryonal sarcoma; Ewing's family of tumours; Microglandular adenosis; Malignant germ cell tumours; Mesenchymal cell neoplasm; Retroperitoneal leiomyosarcomas; Pancreatic mucinous cystadenomas; Reticular perineurioma; Sm-Ahnmd; Renal cell carcinomas (RCC); Aleukemic mast cell leukemias; Acute myeloblastic leukemias with maturation; Acute myeloid leukemias (AML) with T(8;21)(q22;q22) translocation; Acute myeloid leukemias (AML) with abnormal bone marrow eosinophils Inv(16)(p13q22) or T(16;16)(p13;q22); Cutaneous mastocytoma; Isolated bone marrow mastocytosis; Pseudoxanthomatous diffuse cutaneous mastocytosis; Bullous diffuse cutaneous mastocytosis; Systemic mastocytosis with an associated clonal hematologic non-mast cell lineage disease; Smouldering systemic mastocytosis; Nodular urticaria pigmentosa; Plaque-form urticaria pigmentosa; Typical urticaria pigmentosa; Lymphoadenopathic mastocytosis with eosinophilia; Classic mast cell leukemias

KIT is a known oncoprotein (OP). Cancer-related mutations in human tumours point to a gain of function of the protein kinase. The active form of the protein kinase normally acts to promote tumour cell proliferation. Gastrointestinal Stromal tumour (GANT, GIST) is a soft tissue sarcoma growing from the stomach, intestines, or rectum. Gastrointestinal stromal tumour (GIST) has correlated with deletion of residues 550-558, 551-555, 559-560, and 559 while common mutations in GIST are K550I, V559A, and V559D. Mastocytosis is a rare condition arising from an overproduction of mast cells in the body. Seminoma is a rare cancer of the germ-line, affecting the testis, lymph node, prostate, or mediastinum. Germ Cell tumours can affect the testis, ovaries, and lymph node tissues. Leiomyosarcoma is a rare sarcoma of the smooth muscle cells which can also affect the lung, liver, blood vessels, or other soft tissues. Thymic Carcinoma can affect the brain, thymus, and thyroid tissues and it is related to adenoid cystic carcinoma. Urticaria Pigmentosa is a very rare skin disorder where the accumulation of mast cells in the skin results in an overactive immune response, and hives. Dysgerminoma is a germ line tumour that typically only affects ovaries. Uterine Sarcoma is a rare malignant tumour of the connective tissue or smooth muscle in the uterus. Myelofibrosis (MYELOF), is characterized by the bone marrow being superimposed by scar tissue leading to anemia. Teratoma is a tumour that has multiple germ layers, and is often characterized as an encapsulated tumour. Carney Triad is related to the gastrointestinal stromal tumour and paranglioma disorders. Carney Triad is often characterized by mediastinal anomalies, and arrhythmia. The rare disorder Desmoid tumour is an abnormal growth of connective tissues which is highly aggressive (tissue invasion) but rarely spread (do not metastasize often). Hypereosinophilic Syndrome (HES) is a rare blood disorder with increased eosinophil levels and can affect lungs, kidneys, heart, and nervous system. Cutaneous Mastocytosis (CM) is a rare cancer with an expanded mastocyst population and can affect skin, bone, and bone marrow. Systemic Mastocytosis (SMCD) is a rare condition leading to expansion of the mastocyst population. Adenoid Cystic Carcinoma is a rare glandular cancer that can affect the salivary gland, lung, and breast. The rare condition Small Cell Carcinoma is a malignant tumour often arising from the lung. Merkel Cell Carcinoma is a form of skin cancer. Core Binding Factor Acute Myeloid Leukemia (CBF-AML) is a form of myeloid leukemia. In AML the R381A or E386A mutations partially impaired KitLG/SCF-induced autophosphorylation. In AML the I571A or L939A mutations can partly inhibit SH2B2/APS binding, but in conjunction the mutations will fully abrogate it. The S741A and S746A mutations in conjunction abrogated the inhibiting characteristic of PKC/PRKCA, allowing kinase phosphotransferase activity. A K623M mutation increased the strength AML bound MPDZ. Autophosphorylation at Tyr-900 can occur with a Y823F mutation in AML. The rare mastocyst cell carcinoma, Indolent Systemic Mastocytosis is related to systemic mastocytosis and mastocytosis. Thymic Epithelial tumour is a rare disease related to thymoma and breast cancer. Aggressive Systemic Mastocytosis (ASM) is a rare condition with symptoms including pulmonary infiltrates, respiratory failure, and bone fragility. The rare condition Polymorphous Low-Grade Adenocarcinoma (PLGA) is an asymptomatic, slow growing adenocarcinoma. Liposarcoma is a rare sarcoma stemming from fat tissue. Sarcomatoid Renal Cell Carcinoma is related to the spindle cell carcinoma and sarcoma conditions. Thymic Epithelial Neoplasm (TEN) is a cancer related to breast cancer and thymic epithelial tumours. TEN is a rare disease and can affect thymus, lung, and endothelial tissues. Juvenile Nasopharyngeal Angiofibroma (JNA) is a rare condition related to familial adenomatous polyposis and nasopharyngitis. Sinonasal Undifferentiated Carcinoma is a rare carcinoma developing from the sinus, and can affect skin and liver. Dermatofibrosarcoma Protuberans (DFSP) is a rare sarcoma that can also affect breast and lung tissues. Perineurioma is rare and relates to the granular cell tumour and neurofibromatosis disorders. Embryonal Sarcoma is a rare sarcoma, is related to rhabdomyosarcoma, and it can affect lung, liver, and kidney tissues. Ewing's Family of tumours is a rare cancer disease that is similar to medullablastoma and cerebral primitive neuroectodermal tumour. Malignant Germ Cell tumour is related to the germ cell tumours and gonadoblastoma disorders. Malignant Germ Cell tumour can affect ovaries, testis, and lymph nodes. The rare condition Renal Cell Carcinoma (RCC) is a form of kidney cancer arising from the proximal renal tube. Aleukemic Mast Cell Leukemia has a relation to the mast-cell leukemia and leukemia disorders. Acute Myeloblastic Leukemia with Maturation is a form of AML and affects myeloid tissue. Acute Myeloid Leukemia with T(8;21)(q22;q22) Translocation has a relation to the juvenille myelomonocytic leukemia and myeloid sarcoma disorders. Acute Myeloid Leukemia with Abnormal Bone Marrow Eosinophils Inv(16)(p13q22) or T(16;16)(p13;q22) can affect myeloid, bone marrow, and bone tissues. It is a rare cancer that has a relation to myeloid sarcoma and acute myeloid leukemia disorders. Cutaneous Mastocytoma is characterized by hot/cold flashes, migraines, and acute abdominal pain. Isolated Bone Marrow Mastocytosis can affect bone marrow, bone, and skin. Pseudoxanthomatous Diffuse Cutaneous Mastocytosis is characterized by dermal infiltration, vesicle detachment, and mastocytosis. Bullous Diffuse Cutaneous Mastocytosis can be characterized by symptoms including erythematous lesions, and vesicle detachment. Systemic Mastocytosis with an Associated Clonal Hematologic Non-Mast Cell Lineage Disease is a rare disease characterized by symptoms including hypereosinophilia, acute leukemia, and myeloproliferative syndrome. Smouldering Systemic Mastocytosis is a rare condition affecting lymph node tissues and which has a relation to systemic mastocytosis and mastocytosis. The rare disorder Nodular Urticaria Pigmentosa affects skin, and has a relation to urticaria pigmentosa, and uticaria. Typical Urticaria Pigmentosa is a rare condition affecting skin. Acute Myeloid Leukemia (AML) is a rare blood cancer disease which will displace healthy blood cells and can lead to fever, shortness of breath, fatigue, and easy bruising.
 

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Brain oligodendrogliomas (%CFC= -51, p<0.006); Breast epithelial carcinomas (%CFC= -89, p<0.021); Breast epithelial cell carcinomas (%CFC= -60, p<0.0001); Breast epithelial hyperplastic enlarged lobular units (HELU) (%CFC= -86, p<0.002); Breast non-basal-like cancer (BLC) (%CFC= -50, p<0.0001); Breast stromal cell carcinomas (%CFC= -48, p<0.002); Gastric cancer (%CFC= -50, p<0.007); Malignant pleural mesotheliomas (MPM) tumours (%CFC= -73, p<0.008); Papillary thyroid carcinomas (PTC) (%CFC= -73, p<0.001); Pituitary adenomas (ACTH-secreting) (%CFC= -90); Skin melanomas - malignant (%CFC= +148, p<0.0001); Skin squamous cell carcinomas (%CFC= -63, p<0.008); Uterine leiomyomas from fibroids (%CFC= -60, p<0.042); and Vulvar intraepithelial neoplasia (%CFC= -50, p<0.003). The COSMIC website notes an up-regulated expression score for KIT in diverse human cancers of 326, which is 0.7-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 0 for this protein kinase in human cancers was 100% lower than the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice support a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 1.31 % in 57908 diverse cancer specimens. This rate is 17.5-fold higher than the average rate of 0.075 % calculated for human protein kinases in general.

Highest percent mutation rates per 100 amino acids length in human cancers: 4.84 % in 9010 soft tissue cancers tested; 1.81 % in 12309 haematopoietic and lymphoid cancers tested; 0.94 % in 1854 large intestine cancers tested; 0.74 % in 208 thyroid cancers tested; 0.7 % in 5119 skin cancers tested; 0.23 % in 537 bone cancers tested; 0.2 % in 890 stomach cancers tested; 0.19 % in 1365 ovary cancers tested; 0.15 % in 1598 kidney cancers tested; 0.15 % in 1300 liver cancers tested; 0.12 % in 3399 lung cancers tested; 0.11 % in 2347 breast cancers tested; 0.08 % in 1355 pancreas cancers tested; 0.06 % in 2529 central nervous system cancers tested.

Most frequent mutations with the number of reports indicated in brackets: D816V (1486); D816? (195); V559D (230); V560D (172); L576P (186); W557R (118); D816Y (54); V559A (53).

Over a hundred complex mutations and over 500 deletions mutations are concentration between amino acid residues Y553 to K558, which is located just before the protein kinase catalytic domain. The Y503 site has over 380 insertions mutations.