Genomic and biological characterization of exon 4 KRAS mutations in human cancer.
Genomic and biological characterization of exon 4 KRAS mutations in human cancer.
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DOI：
10.1158/0008-5472.can-10-0192
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发表时间：
2010-07-15
期刊：
影响因子：
11.2
通讯作者：
Solit DB
中科院分区：
文献类型：
--
作者：
Janakiraman M;Vakiani E;Zeng Z;Pratilas CA;Taylor BS;Chitale D;Halilovic E;Wilson M;Huberman K;Ricarte Filho JC;Persaud Y;Levine DA;Fagin JA;Jhanwar SC;Mariadason JM;Lash A;Ladanyi M;Saltz LB;Heguy A;Paty PB;Solit DB
RAS蛋白突变在人类癌症中广泛存在。在确认KRAS突变是EGFR靶向治疗反应的预测生物标志物的推动下，最近对RAS途径突变进行了有限的临床测试。我们进行了一项多平台的基因组分析，以无偏见的方式表征结直肠肿瘤和其他实体肿瘤中RAS通路改变的生物学、生化和预后意义。KRAS编码外显子4的突变被发现在结直肠癌患者中普遍发生，并预测更有利的临床结果。外显子4 KRAS突变均位于氨基酸残基K117和A146，在等基因模型中与较低水平的GTP结合RAS相关。在人类肿瘤和肿瘤细胞系中，这些相同的突变也经常伴随着纯合子的转化和基因拷贝数的增加。携带外显子4 KRAS突变的模型显示出MEK依赖和对EGFR靶向药物的耐药性。我们的发现表明，RAS突变在肿瘤中不是一个二元变量，突变等位基因的多样性和基因拷贝数的可变性也可能导致癌症患者临床结果的异质性。这些结果也为更广泛的KRAS检测提供了理论基础，超越了外显子2和3上最常见的热点等位基因。
Mutations in RAS proteins occur widely in human cancer. Prompted by confirmation of KRAS mutation as a predictive biomarker of response to EGFR targeted therapies, limited clinical testing for RAS pathway mutations has recently been adopted. We performed a multiplatform genomic analysis to characterize, in a non-biased manner, the biologic, biochemical and prognostic significance of Ras pathway alterations in colorectal tumors and other solid tumor malignancies. Mutations in coding exon 4 of KRAS were found to occur commonly and to predict for a more favorable clinical outcome in patients with colorectal cancer. Exon 4 KRAS mutations, all of which were identified at amino acid residues K117 and A146, were associated with lower levels of GTP-bound RAS in isogenic models. These same mutations were also often accompanied by conversion to homozygosity and increased gene copy number, in both human tumors and tumor cell lines. Models harboring exon 4 KRAS mutations exhibited MEK-dependence and resistance to EGFR-targeted agents. Our findings suggest that RAS mutation is not a binary variable in tumors, and that the diversity in mutant alleles and variability in gene copy number may also contribute to the heterogeneity of clinical outcomes observed in cancer patients. These results also provide a rationale for broader KRAS testing beyond the most common hotspot alleles in exons 2 and 3.