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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Somatic FGF9 mutations in colorectal and endometrial carcinomas associated with membranous β-catenin
Human Mutation, Volume 29, No. 3, Year 2008
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Description
We previously described striking molecular features including high frequency of membranous β-catenin in subsets of familial colon cancers with as yet unknown predisposition. We hypothesized that such tumors might carry mutations in Wnt/β-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 (FGF9Δ205-208) mutations should negatively impact ligand's interaction with receptor, while p.G84E and p.E142X (FGF9Δ142-208) mutations should interfere with ligand folding. Consistent with these structural predictions, the p.V192M, p.D203G, and p.L188YfsX18 (FGF9Δ205-208) 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 β-catenin expression and the absence of mutation in the β-catenin gene (CTNNB1). These data suggest that FGF9 plays a role in colorectal and endometrial carcinogenesis. © 2007 Wiley-Liss, Inc.
Authors & Co-Authors
Abdel-Rahman, Wael M.
Finland, Helsinki
Helsingin Yliopisto
United Arab Emirates, Sharjah
University of Sharjah
Kalinina, Juliya
United States, New York
Nyu Grossman School of Medicine
Shoman, Soheir H.
Egypt, Giza
National Cancer Institute
Eissa, Saad Sayed
Egypt, Giza
National Cancer Institute
Ollikainen, Miina
Finland, Helsinki
Helsingin Yliopisto
Elomaa, Outi
Finland, Helsinki
Helsingin Yliopisto
Eliseenkova, Anna V.
United States, New York
Nyu Grossman School of Medicine
Bützow, Ralf
Finland, Helsinki
Helsinki University Hospital
Mohammadi, Moosa
United States, New York
Nyu Grossman School of Medicine
Peltomäki, Päivi T.
Finland, Helsinki
Helsingin Yliopisto
Statistics
Citations: 34
Authors: 10
Affiliations: 5
Identifiers
Doi:
10.1002/humu.20653
ISSN:
10597794
Research Areas
Cancer
Genetics And Genomics