Activating K-Ras mutations outwith 'hotspot' codons in sporadic colorectal tumours - implications for personalised cancer medicine
Activating K-Ras mutations outwith 'hotspot' codons in sporadic colorectal tumours - implications for personalised cancer medicine
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DOI：
10.1038/sj.bjc.6605534
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发表时间：
2010-02-16
影响因子：
8.8
通讯作者：
Wolf, C. R.
中科院分区：
文献类型：
--
作者：
Smith, G.;Bounds, R.;Wolf, C. R.
背景技术背景：结直肠癌患者对EGFR靶向治疗的反应已令人信服地与Kirsten-Ras（K-Ras）突变状态相关。目前用于患者选择的强制性突变检测仅限于K-Ras“热点”密码子12和13。方法：对106例结直肠肿瘤进行额外K-Ras突变筛查，转化和Ras GT3激活试验中的表型比较，以及通过微阵列分析鉴定的单个K-Ras突变体诱导的基因和途径变化。结果：106例肿瘤中发现4个K-Ras突变（Leu（19）Phe（1/106），Lys（117）Asn（1/106），Ala（146）Thr（7/106）和Arg（164）Gln（1/106））。Lys（117）Asn和Ala（146）Thr具有与热点突变相似的表型，而Leu（19）Phe具有减弱的表型，Arg（164）Gln突变在表型上与wt K-Ras等同。我们还确定了一个新的K-Ras基因扩增事件，目前在约2%的tumors.CONCLUSIONS：与以前描述的热点密码子的突变outwith的识别增加了K-Ras突变负担在结直肠肿瘤的三分之一。因此，未来的突变筛查，以促进最佳的患者选择治疗EGFR靶向治疗，应扩展到密码子146，此外，应考虑与个别K-Ras突变相关的独特的分子特征。英国癌症杂志（2010）102，693-703。doi：10.1038/sj.bjc.6605534 www.bjcancer.com（C）2010英国癌症研究
BACKGROUND: Response to EGFR-targeted therapies in colorectal cancer patients has been convincingly associated with Kirsten-Ras (K-Ras) mutation status. Current mandatory mutation testing for patient selection is limited to the K-Ras 'hotspot' codons 12 and 13.METHODS: Colorectal tumours (n = 106) were screened for additional K-Ras mutations, phenotypes compared in transformation and Ras GTPase activating assays and gene and pathway changes induced by individual K-Ras mutants identified by microarray analysis. Taqman-based gene copy number and FISH analyses were used to investigate K-Ras gene amplification.RESULTS: Four additional K-Ras mutations (Leu(19)Phe (1 out of 106 tumours), Lys(117)Asn (1 out of 106), Ala(146)Thr (7 out of 106) and Arg(164)Gln (1 out of 106)) were identified. Lys(117)Asn and Ala(146)Thr had phenotypes similar to the hotspot mutations, whereas Leu(19)Phe had an attenuated phenotype and the Arg(164)Gln mutation was phenotypically equivalent to wt K-Ras. We additionally identified a new K-Ras gene amplification event, present in approximately 2% of tumours.CONCLUSIONS: The identification of mutations outwith previously described hotspot codons increases the K-Ras mutation burden in colorectal tumours by one-third. Future mutation screening to facilitate optimal patient selection for treatment with EGFR-targeted therapies should therefore be extended to codon 146, and in addition should consider the unique molecular signatures associated with individual K-Ras mutations. British Journal of Cancer (2010) 102, 693-703. doi:10.1038/sj.bjc.6605534 www.bjcancer.com (C) 2010 Cancer Research UK