SomaticFGF9mutations in colorectal and endometrial carcinomas associated with membranousβ-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.

MicroRNA-140-5p inhibits hepatocellular carcinoma by directly targeting the unique isomerase Pin1 to block multiple cancer-driving pathways

“…These results are consistent with the previous findings that miR-140-5p has other targets such as TGFβR1 and FGF91. Interestingly, some downstream targets of TGFβR1 and FGF9 such as TGF-β and the ERK/MAPK signaling pathways6263 are regulated by Pin128. For example, in our study, miR-140-5p suppressed the expression of a few endogenous ERK/MAPK pathway-related proteins (such as ERK and pERK) (Fig.…”

Distinct Genetic and Epigenetic Signatures of Colorectal Cancers According to Ethnic Origin

“…Our previous findings of mutations in specific genes such as FGF9 could also explain some of these tumors that lack nuclear b-catenin (38). The question remains why b-catenin protein expression should be membranous in a high proportion of colorectal carcinomas of Egyptian and FCCX origin and whether or not a distinct pathogenic mechanism is responsible for the development of this particular phenotype.…”

Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

“…At variance with FGFR genes, FGF mutations are rare in human cancers and their impact on cancer biology is unclear. Indeed, to the best of our knowledge, somatic mutations have been described only for FGF9 in colorectal and endometrial cancers [57]. They are predicted to result in loss-of-function and it is not known whether these mutations participate in tumor formation.…”