title: Somatic FGF9 mutations in colorectal and endometrial carcinomas associated with membranous beta-catenin.
abstract: We previously described striking molecular features including high frequency of membranous beta-catenin in subsets of familial colon cancers with as yet unknown predisposition. We hypothesized that such tumors might carry mutations in Wnt/beta-catenin target genes. Fibroblast growth factor 9 (FGF9) was an attractive target, as it maps to a common area of loss of heterozygosity (LOH) in colorectal carcinomas on 13q12.11. Here, we report, for the first time, the occurrence of FGF9 mutations in human cancers. We found a total of six distinct FGF9 mutations including one frameshift, four missense, and one nonsense, in 10 (six colorectal and four endometrial) out of 203 tumors and cell lines. The frameshift mutation was detected in five different tumors. Mapping of these mutations onto the crystal structure of FGF9 predicted that they should all lead to loss of function albeit through variable mechanisms. The p.R173K mutation should diminish ligand affinity for heparin/heparan sulfate, the p.V192M, p.D203G, and p.L188YfsX18 (FGF9(Delta205-208)) mutations should negatively impact ligand's interaction with receptor, while p.G84E and p.E142X (FGF9(Delta142-208)) mutations should interfere with ligand folding. Consistent with these structural predictions, the p.V192M, p.D203G, and p.L188YfsX18 (FGF9(Delta205-208)) mutations impaired the ability of ligand to activate mitogen-activated protein kinase (MAPK) cascade in cultured cells expressing FGF receptors. LOH was observed in seven out of nine FGF9 mutant tumors, supporting the predicted loss of function. Interestingly, eight out of 10 (80%) of the FGF9 mutant tumors showed normal membranous beta-catenin expression and the absence of mutation in the beta-catenin gene (CTNNB1). These data suggest that FGF9 plays a role in colorectal and endometrial carcinogenesis.
authors.affiliation: Department of Medical Genetics, University of Helsinki, Helsinki, Finland. Wael.Abdel-Rahman@helsinki.fi
authors.forename: Wael M
authors.initials: WM
authors.lastname: Abdel-Rahman
authors.forename: Juliya
authors.initials: J
authors.lastname: Kalinina
authors.forename: Soheir
authors.initials: S
authors.lastname: Shoman
authors.forename: Saad
authors.initials: S
authors.lastname: Eissa
authors.forename: Miina
authors.initials: M
authors.lastname: Ollikainen
authors.forename: Outi
authors.initials: O
authors.lastname: Elomaa
authors.forename: Anna V
authors.initials: AV
authors.lastname: Eliseenkova
authors.forename: Ralf
authors.initials: R
authors.lastname: Bützow
authors.forename: Moosa
authors.initials: M
authors.lastname: Mohammadi
authors.forename: Päivi
authors.initials: P
authors.lastname: Peltomäki
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D051525:Fibroblast Growth Factor 9 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D019656:Loss of Heterozygosity; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D004273:DNA, Neoplasm; C496459:FGF9 protein, human; D051525:Fibroblast Growth Factor 9; D008024:Ligands; D008565:Membrane Proteins; D051153:Wnt Proteins; D051176:beta Catenin