Loss-of-function fibroblast growth factor receptor-2 mutations in melanoma.
Loss-of-function fibroblast growth factor receptor-2 mutations in melanoma.
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DOI：
10.1158/1541-7786.mcr-08-0021
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发表时间：
2009-01
期刊：
影响因子：
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通讯作者：
Pollock PM
中科院分区：
文献类型：
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作者：
Gartside MG;Chen H;Ibrahimi OA;Byron SA;Curtis AV;Wellens CL;Bengston A;Yudt LM;Eliseenkova AV;Ma J;Curtin JA;Hyder P;Harper UL;Riedesel E;Mann GJ;Trent JM;Bastian BC;Meltzer PS;Mohammadi M;Pollock PM
我们报告说，10%的黑色素瘤肿瘤和细胞系在成纤维细胞生长因子受体2（FGFR2）基因中含有突变。这些新的突变包括3个截短突变和20个错义突变，发生在FGFR 2以及所有4个FGFR的进化保守残基上。突变谱是紫外线辐射诱导的突变谱的特征。将这些突变定位到FGFR 2的已知晶体结构上，然后进行体外和体内研究，结果表明，这些突变通过几种不同的机制导致受体功能丧失，包括配体结合亲和力丧失、受体二聚化受损、细胞外结构域不稳定和激酶活性降低。据我们所知，这是第一次证明癌症中IV类受体酪氨酸激酶的功能丧失突变。考虑到我们最近在子宫内膜癌中发现的激活FGFR2突变，我们认为FGFR2可能加入了在癌症中发挥背景依赖性相反作用的基因列表。
We report that 10% of melanoma tumors and cell lines harbor mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. These novel mutations include three truncating mutations and 20 missense mutations occurring at evolutionary conserved residues in FGFR2 as well as among all four FGFRs. The mutation spectrum is characteristic of those induced by UV radiation. Mapping of these mutations onto the known crystal structures of FGFR2 followed by in vitro and in vivo studies show that these mutations result in receptor loss of function through several distinct mechanisms, including loss of ligand binding affinity, impaired receptor dimerization, destabilization of the extracellular domains, and reduced kinase activity. To our knowledge, this is the first demonstration of loss-of-function mutations in a class IV receptor tyrosine kinase in cancer. Taken into account with our recent discovery of activating FGFR2 mutations in endometrial cancer, we suggest that FGFR2 may join the list of genes that play context-dependent opposing roles in cancer.