Somatic FGF9 mutations in colorectal and endometrial carcinomas associated with membranous β-catenin
Somatic FGF9 mutations in colorectal and endometrial carcinomas associated with membranous β-catenin
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DOI：
10.1002/humu.20653
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发表时间：
2008-03-01
期刊：
影响因子：
3.9
通讯作者：
Peltomaki, Paivi
中科院分区：
文献类型：
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作者：
Abdel-Rahman, Wael M.;Kalinina, Juliya;Peltomaki, Paivi
我们先前描述了显著的分子特征，包括高频率的膜性β-连环素，在易感性尚不清楚的家族性结肠癌亚群中。我们推测，这种肿瘤可能携带Wnt/β-catenin靶基因突变。成纤维细胞生长因子9(FGF9)是一个很有吸引力的靶点，因为它定位于13q12.11的结直肠癌中常见的杂合性缺失(LOH)区域。在这里，我们首次报告了FGF9突变在人类癌症中的发生。我们在203个肿瘤和细胞系中的10个(6个结直肠和4个子宫内膜)中发现了总共6个不同的FGF9突变，包括1个移码，4个错义和1个无义突变。在五种不同的肿瘤中检测到移码突变。将这些突变映射到FGF9的晶体结构上预测它们都应该导致功能丧失，尽管是通过不同的机制。P.R173K突变会降低配体与肝素/硫酸肝素的亲和力，p.V192M、p.D203G和p.L188YfsX18(FGF9(Delta 205-208))突变会对配体与受体的相互作用产生负面影响，而p.G84E和p.E142X(FGF9(Delta 142-208))突变会干扰配体折叠。与这些结构预测一致，p.V192M、p.D203G和p.L188YfsX18(FGF9(Delta 205-208))突变削弱了配体激活有丝分裂原的能力，激活的蛋白激酶(MAPK)在表达成纤维细胞生长因子受体的培养细胞中级联。在9个FGF9突变肿瘤中有7个观察到LOH，支持预测的功能丧失。有趣的是，在10个FGF9突变肿瘤中，有8个(80%)显示膜性β-连环蛋白表达正常，而β-连环蛋白基因(CTNNB1)没有突变。这些数据表明，FGF9在结直肠癌和子宫内膜癌的发生中起作用。
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(Delta 205-208)) mutations should negatively impact ligand's interaction with receptor, while p.G84E and p.E142X (FGF9(Delta 142-208)) mutations should interfere with ligand folding. Consistent with these structural predictions, the p.V192M, p.D203G, and p.L188YfsX18 (FGF9(Delta 205-208)) 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.