Cancer, bone, development, and endocrine disorders

Osteoglophonic dysplasia (OGD); Kallmann syndrome; Craniosynostosis (CSO); Hartsfield syndrome; Trigonocephaly 1 (HRTFDS); Cleft lip; Synostosis; Hypogonadotropic hypogonadism 2 with or without Anosmia (HH2); Crouzon syndrome (CFD1); Hypochondroplasia (HCH); Antley-Bixler syndrome; Infectious mononucleosis (ACS5); Septo-optic dysplasia (SOD); Kallmann syndrome 1; Achondroplasia (ACH); Saethre-Chotzen syndrome (SCS); Acrocephalosyndactylia (ACS1); Muenke syndrome; Plagiocephaly; Radioulnar synostosis; Pfeiffer syndrome Type 1 (PS); FGFR-related craniosynostosis syndromes; Kallmann syndrome 2; Hypogonadotropic Hypogonadism 8 with or without Anosmia; Hypogonadotropic hypogonadism 17 with or without Anosmia; Tooth agenesis, selective, 1, with or without orofacial cleft; FGFR1-related Craniosynostosis; Trigonocephaly, nonsyndromic; FGFR1-related isolated gonadotropin-releasing hormone deficiency; FGFR1-related isolated gonadotropin-releasing hormone deficiency

Osteoglophonic Dysplasia (OGD) is characterized by abnormal bone growth, craniofacial deformations, and dwarfism. In OGD FGF-2 mediated activity and basal activity are increased with an FGFR1 mutation of Y374C. The rare disease Kallmann Syndrome can manifest with delayed puberty, impaired sense of smell, colour blind, cleft lip, hearing loss, kidney development issues, and infertility. Craniosynostosis (CSO) is a disorder arising from premature fusion of fibrous joints in the skull resulting in abnormal skull shape, yet often allowing full brain development. Sometimes many fusions occur in CSO, resulting in restricted brain growth leading to cognitive impairment and sometimes seizures and blindness. Hartsfield Syndrome (HRTFDS) is characterized by respiratory distress, and holoprosencephaly (facial malformation). HRTFDS can affect the olfactory bulb and lung tissues. Trigonocephaly 1 is a rare eye disease. Synostosis is rare disease resulting in the fusion of two bones, typically cranial bones. Hypogonadotropic Hypogonadism 2 with or Without Anosmia (HH2) is a disorder affecting the sexual organs, and is characterized by lack of sex hormone production. In HH2 a similar phenotype to normosmic idiopathic hypogonadotropic hypogonadism is observed with a G48S mutation. In HH2 incomplete glycosylation and reduced cell surface expression of FGFR1 can occur with the Y99C, Y228D, I239T mutations. In HH2 the A167S mutation can be associated with corpus callosum agenesis, cleft palate, unilateral deafness, and fusion of the fourth and fifth metacarpal bones. In HH2 severe ear defects occur with the C178S, and R622G mutations. In HH2 improper folding may occur with the G237S mutation. In HH2 receptor affinity for fibroblast growth factor is decreased with a R250Q mutation. In HH2 a phenotype similar to Kallmann syndrome occurs with a G348R mutation. Bimanual synkinesis occurs in HH2 with a V607M mutation. Tyrosine kinase activity in HH2 is impaired with the K618N, P722H, and N724K mutations. A patient suffering from HH2 had a cleft palate, iris coloboma, and unilateral absence of nasal cartilage had a mutation, P772S. Crouzon Syndrome is a rare disease arising from premature fusion of skull bones resulting in facial abnormalities. Hypochondroplasia (HCH) is a rare bone disease characterized by dwarfism. Antley-Bixler Syndrome is a rare bone disease resulting in malformations along the majority of the body. Infectious Mononucleosis (ACS5) inhibits the normal formation of the skull resulting in bulging, wide-set eyes, and an underdeveloped upper jaw. ACS5 can affect pharynx, bone, and spleen. Septo-Optic Dysplasia (SOD) is a rare genetic disorder which is characterized by abnormal development of the optic disk, absence of agenesis, defective pituitary gland, blindness, issues focusing eyes, and periodically intellectual disability. Achondroplasia (ACH) is a rare disease where conversion of cartilage to bone is inhibited. Saethre-Chotzen Syndrome (SCS) is a rare bone disease where skull bones fuse prematurely during development. Acrocephalosyndactylia (ACS1) is also a rare bone disease where skull bones fuse prematurely during development, and can affect bone, eye, or ovary tissues. Muenke Syndrome is a rare disease where the premature fusing of the coronal structure occurs, leading to facial abnormalities. Muenke Syndrome can also affect hands, feet, induce hearing loss, and result in developmental delay. Plagiocephaly is a rare disease where there is asymmetrical flattening of one side of a neonate's head. Radioulnar Synostosis is related to synostosis and craniosynostosis. Pfeiffer Syndrome Type 1 (PS) is a rare bone disease leading to proptosis (forward setting of the eye, past the eyelid), low set ears, and brachydactylyl (short fingers). A gain of function mutation in (PS) is P252R. Tooth Agenesis, Selective, 1, with or Without Orofacial Cleft is a rare disease and may or may not be characterized by an orofacial cleft, but most likely will have facial deformations, partial mandibula absence, and tooth shape anomaly. Trigonocephaly, Nonsyndromic a rare bone disease resulting in the premature fusion of the metopic structure (part of the forehead).
 

Myeloid neoplasm associated with FGFR1 rearrangement; 8p11 myeloproliferative syndrome; Myeloproliferative disorder; Colorectal cancer; Gliomatosis cerebri; Osteochondromas; Lobular neoplasia; Pilocytic astrocytomas; Gliosarcomas; Giant cell glioblastomas

FGFR1 may be an oncoprotein (OP). The active form of the protein kinase normally acts to promote tumour cell proliferation. Myeloid Neoplasm Associated with FGFR1 gene rearrangement and is a rare disease that typically affects myeloid tissues. Myeloid Neoplasm Associated with Fgfr1 Rearrangement is related to 8p11 myeloproliferative syndrome and chromosome 8p11 myeloproliferative syndrome. 8p11 Myeloproliferative Syndrome is a rare blood cancer forming either myeloid or lymphoid cell cancer. Myeloproliferative Disorder is a rare cancer disease affecting bone, bone marrow, and myeloid tissues. Myeloproliferative Disorder is related to Alzheimer’s and G protein signalling H-RAS regulation pathway. Gliomatosis Cerebri is a rare brain cancer resulting in a diffuse tumour that is therefore difficult to treat. Osteochondroma is a rare bone tumour. Lobular Neoplasia is a breast cancer, and is related to breast fibroadenoma. Pilocytic Astrocytoma is a benign tumour of the brain or spinal cord which is slow growing. Gliosarcoma is another rare cancer of the brain, but arising from glial cells. Giant Cell Glioblastoma is a multinucleated cell that has a large diameter.
 

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: Bladder carcinomas (%CFC= -47, p<0.01); Brain glioblastomas (%CFC= -72, p<0.0001); Breast epithelial cell carcinomas (%CFC= +47, p<0.029); Clear cell renal cell carcinomas (cRCC) stage I (%CFC= +308, p<0.0006); Colorectal adenocarcinomas (early onset) (%CFC= +103, p<0.0001); Gastric cancer (%CFC= +69, p<0.033); Pituitary adenomas (aldosterone-secreting) (%CFC= +71, p<0.0002); Prostate cancer - primary (%CFC= -56, p<0.0001); Skin fibrosarcomas (%CFC= +268, p<0.007); Skin melanomas (%CFC= -53, p<0.032); Uterine fibroids (%CFC= +55, p<0.034); andVulvar intraepithelial neoplasia (%CFC= -47, p<0.001). The COSMIC website notes an up-regulated expression score for FGFR1 in diverse human cancers of 490, which is close to 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 average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis. FGFR1 phosphotransferase activity can be abrogated with K514A and D623A mutations. Autophosphorylation and kinase activity can be inhibited with a mutation at both Y653F and Y654F. The first autophosphorylation can be sped up, but the second autophosphorylation event inhibited entirely with a N546K mutation. The R577E mutation can lead to strongly decreased autophosphorylation in response to FGF signalling. PLCG1 interaction with FGFR1 can be inhibited with mutation of R609V and D755V. The Y766F mutation can inhibit PLCG1 and SHB interaction with FGFR1, decrease FRS2 phosphorylation, and induce RAS or MAPK signalling, leading to cell proliferation.

Percent mutation rates per 100 amino acids length in human cancers: 0.1 % in 30128 diverse cancer specimens. This rate is only 29 % 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: 0.41 % in 1560 large intestine cancers tested; 0.31 % in 856 stomach cancers tested; 0.22 % in 1447 skin cancers tested; 0.19 % in 708 endometrium cancers tested; 0.19 % in 2189 central nervous system cancers tested; 0.09 % in 2253 lung cancers tested; 0.07 % in 2143 breast cancers tested.

Most frequent mutations with the number of reports indicated in brackets: N546K (19); K656E (8); K656M (4).

Only 1 deletion, 2 insertions and no complex mutations are noted on the COSMIC website.