Activating K-Ras mutations outwith 'hotspot' codons in sporadic colorectal tumours - implications for personalised cancer medicine

被引:141
作者
Smith, G. [1 ]
Bounds, R. [1 ]
Wolf, H. [1 ]
Steele, R. J. C. [2 ]
Carey, F. A. [3 ]
Wolf, C. R. [1 ,4 ]
机构
[1] Ninewells Hosp & Med Sch, Biomed Res Inst, Dundee DD1 9SY, Scotland
[2] Univ Dundee, Dept Surg & Mol Oncol, Dundee DD1 9SY, Scotland
[3] Ninewells Hosp & Med Sch, Dept Mol & Cellular Pathol, Dundee DD1 9SY, Scotland
[4] Ninewells Hosp & Med Sch, CRUK Mol Pharmacol Unit, Dundee DD1 9SY, Scotland
关键词
K-Ras; mutation; colorectal tumour; gene amplification; personalised medicine; SIGNALING PATHWAY; COSTELLO-SYNDROME; POINT MUTATION; COLON-CANCER; KIRSTEN-RAS; B-RAF; CETUXIMAB; KRAS; CELLS; GENE;
D O I
10.1038/sj.bjc.6605534
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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
引用
收藏
页码:693 / 703
页数:11
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