A comprehensive survey of Ras mutations in cancer.
A comprehensive survey of Ras mutations in cancer.
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DOI：
10.1158/0008-5472.can-11-2612
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发表时间：
2012-05-15
期刊：
影响因子：
11.2
通讯作者：
Mattos C
中科院分区：
文献类型：
--
作者：
Prior IA;Lewis PD;Mattos C
所有哺乳动物细胞都表达三种密切相关的Ras蛋白：H-Ras、K-Ras和N-Ras，当密码子12、13或61处突变激活时，它们会促进肿瘤发生。尽管亚型之间高度相似，但K-Ras突变在癌症中更频繁地观察到，并且每种亚型显示出与特定癌症类型的优先偶联。我们已经检查了从大规模肿瘤分析中策划的Ras亚型的突变谱，发现每个亚型都表现出令人惊讶的独特密码子突变和氨基酸取代偏倚。考虑到这些突变发生在三种同种型之间具有100%氨基酸序列同一性的区域中，这些突变是出乎意料的。重要的是，许多突变偏倚不是由于暴露于诱变剂的差异，因为在特定癌症类型中进行比较时，这些模式仍然很明显。我们讨论了潜在的遗传和表观遗传机制，以及蛋白质结构和信号传导中的同种型特异性差异，这些差异可能促进这些不同的突变模式和与特定癌症的差异偶联。
All mammalian cells express three closely related Ras proteins: H-Ras, K-Ras and N-Ras that promote oncogenesis when mutationally activated at codons 12, 13 or 61. Despite a high degree of similarity between the isoforms, K-Ras mutations are far more frequently observed in cancer and each isoform displays preferential coupling to particular cancer types. We have examined the mutation spectra of Ras isoforms curated from large-scale tumour profiling and found that each isoform exhibits surprisingly distinctive codon mutation and amino acid substitution biases. These were unexpected given that these mutations occur in regions that share 100% amino acid sequence identity between the three isoforms. Importantly, many of the mutational biases were not due to differences in exposure to mutagens because the patterns were still evident when compared within specific cancer types. We discuss potential genetic and epigenetic mechanisms together with isoform-specific differences in protein structure and signalling that may promote these distinct mutation patterns and differential coupling to specific cancers.