Recurrent KRAS codon 146 mutations in human colorectal cancer

Sarah Edkins, Sarah O'Meara, Adrian Parker, Claire Stevens, Marcelo Reis, Siân Jones, Chris Greenman, Helen Davies, Gillian Dalgliesh, Simon Forbes, Chris Hunter, Raffaella Smith, Philip Stephens, Peter Goldstraw, Andrew Nicholson, Leung Chan Tsun, Victor E. Velculescu, Tsan Yuen Siu, Yi Leung Suet, Michael R. StrattonP. Andrew Futreal

Research output: Contribution to journalArticle

Abstract

An activating point mutation in codon 12 of the HRAS gene was the first somatic point mutation identified in a human cancer and established the role of somatic mutations as the common driver of oncogenesis. Since then, there have been over 11,000 mutations in the three RAS (HRAS, KRAS and NRAS) genes in codons 12, 13 and 61 reported in the literature. We report here the identification of recurrent somatic missense mutations at alanine 146, a highly conserved residue in the guanine nucleotide binding domain. In two independent series of colorectal cancers from Hong Kong and the United States we detected KRAS A146 mutations in 7/126 and 2/94 cases, respectively, giving a combined frequency of 4%. We also detected KRAS A146 mutations in 2/40 (5%) colorectal cell lines, including the NCI-60 colorectal cancer line HCC2998. Codon 146 mutations thus are likely to make an equal or greater contribution to colorectal cancer than codon 61 mutations (4.2% in our combined series, 1% in the literature). Lung adenocarcinomas and large cell carcinomas did not show codon 146 mutations. We did, however, identify a KRAS A146 mutation in the ML-2 acute myeloid leukemia cell line and an NRAS A146 mutation in the NALM-6 B-cell acute lymphoblastic leukemia line, suggesting that the contribution of codon 146 mutations is not entirely restricted to colorectal cancers or to KRAS.

Original languageEnglish (US)
Pages (from-to)928-932
Number of pages5
JournalCancer Biology and Therapy
Volume5
Issue number8
DOIs
StatePublished - Aug 2006

Keywords

  • A146
  • Cancer
  • Colorectal
  • KRAS
  • Mutation

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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  • Cite this

    Edkins, S., O'Meara, S., Parker, A., Stevens, C., Reis, M., Jones, S., Greenman, C., Davies, H., Dalgliesh, G., Forbes, S., Hunter, C., Smith, R., Stephens, P., Goldstraw, P., Nicholson, A., Tsun, L. C., Velculescu, V. E., Siu, T. Y., Suet, Y. L., ... Futreal, P. A. (2006). Recurrent KRAS codon 146 mutations in human colorectal cancer. Cancer Biology and Therapy, 5(8), 928-932. https://doi.org/10.4161/cbt.5.8.3251