Cancer, bone disorders

Achondroplasia; Hypochondroplasia; Muenke syndrome; Ladd syndrome; Craniosynostosis; Thanatophoric dysplasia; Epidermal nevus, somatic; Keratosis, seborrheic, somatic; Skeletal dysplasias; Dwarfism; Thanatophoric dysplasia Type 1; Saethre-Chotzen syndrome; Crouzonodermoskeletal syndrome; Thanatophoric dysplasia Type 2; Camptodactyly, tall stature, and hearing loss syndrome; Acanthosis nigricans; Crouzon syndrome; Keratosis; Synostosis; Cherubism; Strabismus; Saddan; Beare-Stevenson Cutis Gyrata syndrome; FGFR-related craniosynostosis syndromes; Nevus sebaceous, somatic; FGFR3-related craniosynostosis; Epidermal nevus; Dermatosis papulosa nigra; Skeletal dysplasia, San Diego Type; Acrocephalosyndactylia; Jackson-Weiss syndrome; Osteoglophonic dysplasia; Polyhydramnios; Osteogenesis imperfecta, Type 1I; Seborrheic keratosis; Plagiocephaly; Radioulnar synostosis; Astigmatism; Craniosynostosis, Type 1; Craniosynostosis 4; Craniosynostosis 3; FGFR3-related isolated coronal synostosis; FGFR3-related lacrimo-auriculo-dento-digital syndrome

Achondroplasia is a bone disease that is characterized by the failed conversion of cartilage into bone during skeletal development. Symptoms of this disease include dwarfism, limited range of motion at the joints, large-size head, small fingers, and normal intelligence. Hypochondroplasia is a type of dwarfism that is also characterized by the failure of cartilage to be converted into bone during development. Hypochondroplasia is similar to achondroplasia, but the symptoms are milder. Hypochondroplasia is inherited in an autosomal dominant manner. Various mutations in the FGFR3 gene are associated with achondroplasia and hypochondroplasia, with the most common being a G380R substitution mutation. Affected individuals have epiphyseal growth plates of their long bones that are abnormal organized, are hypocellular, and display aberrant chondrocyte maturation and development. In vitro and in vivo studies have concluded that FGFR3 acts as an inhibitory factor for chondrocyte proliferation and maturation. Gain-of-function mutations resulting in enhanced kinase catalytic activity of the EGFR3 protein are hypothesized to be the cause of achondroplasia and hypochondroplasia, due to the excessive suppression of chondrocyte proliferation and maturation by the overactive EGFR3 protein. Abnormal EGFR3 activity may have a role in the pathogenesis of achondroplasia and hypochondroplasia.
 

Bladder cancer, somatic; Myelomas; Bladder carcinomas; Papilloma; Osteochondromas; Bladder cancer susceptibility; Colorectal cancer; Cervical cancer; Germ cell tumours; Monoclonal gammopathy of uncertain significance; Spermatocytic seminomas, somatic; Bladder transitional cell papillomas; Cervical cancer, somatic; Gliosarcomas; Giant cell glioblastomas; Male germ cell tumours, somatic; Colorectal cancer, somatic; Testicular tumours, somatic

FGFR3 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. Mutations in the FGFR3 gene that result in overactive or constitutive kinase phosphotransferase activity have been associated with several cancer types as they cause aberrant cell proliferation and differentiation as well as reduced apoptosis. For example, ectopic activation of the FGFR3 protein has been observed in multiple myeloma cancer specimens. Furthermore, dysregulated FGFR3 activity has been observed in 14. 5% of bone marrow samples from patients with multiple myeloma In particular, the multiple myeloma phenotype and progression of the cancer has been associated with the abnormal interaction between FGFR3 and the regulatory subunit of PI3K (P1K3R1). Short interferring RNA (siRNA)-mediated knockdown of PIK3R2 in multiple myeloma cancer cell lines results in increased dowstream ERK activity in response to FGF2 stimulation, indicating a tumour suppressive role for the PIK3R2 protein in the inhibition of MAPK signal activation. Furthermore, dysregulation of oncogenes by translocation of the gene sequence to the immunoglobulin heavy chain locus (14q32) is though to be a primary event in the development of B-cell tumours. Chromosome 4 breakpoints involved in the tumorigenesis of multiple myeloma are concentrated in the 70 kb region ~100 kb centromeric to the FGFR3 gene, indicating that the FGFR3 gene is translocated and contributes to the development of multiple myeloma. This translocation was observed in 3-24% of different groups of multiple myeloma cancer cell lines. In addition, the resultant FGFR3 protein produced by this translocation is predicted to display consitutive kinase catalytic activity, even in the absence of ligands, indicating that the translocation results in oncogenic FGFR3 activity. Mutations in the FGFR3 gene have also been associated with colon cancer, including a E322L substitution mutation in a highly conserved residue (the Glu322 residue is conserved from yeast to human), and a 1-bp deletion mutation (849delC) in exon 7 of the gene which causes a frameshift mutation resulting in the production of a truncated FGFR3 protein.
 

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: Barrett's esophagus epithelial metaplasia (%CFC= -68, p<0.022); Bladder carcinomas (%CFC= +247, p<0.014); Ovary adenocarcinomas (%CFC= +165, p<0.068); Skin melanomas - malignant (%CFC= -95, p<0.017); Uterine fibroids (%CFC= -66, p<0.012); and Uterine leiomyomas (%CFC= +430, p<0.02). The COSMIC website notes an up-regulated expression score for FGFR3 in diverse human cancers of 406, which is 0.9-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 have not yet revealed a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 1.08 % in 40934 diverse cancer specimens. This rate is 14.4-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: 4.87 % in 7248 urinary tract cancers tested; 1.76 % in 2454 skin cancers tested; 0.64 % in 1390 upper aerodigestive tract cancers tested; 0.38 % in 1549 large intestine cancers tested; 0.12 % in 2474 haematopoietic and lymphoid cancers tested; 0.11 % in 1119 prostate cancers tested; 0.06 % in 2909 lung cancers tested.

Most frequent mutations with the number of reports indicated in brackets: S249C (1822); Y373C (574); R248C (398); G370C (158); S371C (55); G697C (44): K650E (79); K650M (82). AA 650 and 697 are in the kinase catalytic domain..

In human tumours, there are two main clusters of mutations at amino acid resdiues 248-249 and 370-390 with point mutations. insertions and deletions also occur in the first cluster, whereas complex mutations also occur within the second main cluster.