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

G. Smith, R. Bounds, H. Wolf, Robert Steele, Francis Carey, Roland Wolf (Lead / Corresponding author)

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    119 Citations (Scopus)

    Abstract

    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

    Original languageEnglish
    Pages (from-to)693-703
    Number of pages11
    JournalBritish Journal of Cancer
    Volume102
    Issue number4
    DOIs
    Publication statusPublished - 16 Feb 2010

    Keywords

    • K-Ras
    • mutation
    • colorectal tumour
    • Gene amplification
    • Personalised medicine
    • Signalling pathway
    • Costello syndrome
    • Point mutation
    • Colon cancer
    • Kirsten Ras
    • B-Raf
    • Cetuximab
    • Cells
    • Gene

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