title: Recurrent KRAS codon 146 mutations in human colorectal cancer.
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.
authors.affiliation: Cancer Genome Project, Welcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Edkins
authors.forename: Sarah
authors.initials: S
authors.lastname: O'Meara
authors.forename: Adrian
authors.initials: A
authors.lastname: Parker
authors.forename: Claire
authors.initials: C
authors.lastname: Stevens
authors.forename: Marcelo
authors.initials: M
authors.lastname: Reis
authors.forename: Siân
authors.initials: S
authors.lastname: Jones
authors.forename: Chris
authors.initials: C
authors.lastname: Greenman
authors.forename: Helen
authors.initials: H
authors.lastname: Davies
authors.forename: Gillian
authors.initials: G
authors.lastname: Dalgliesh
authors.forename: Simon
authors.initials: S
authors.lastname: Forbes
authors.forename: Chris
authors.initials: C
authors.lastname: Hunter
authors.forename: Raffaella
authors.initials: R
authors.lastname: Smith
authors.forename: Philip
authors.initials: P
authors.lastname: Stephens
authors.forename: Peter
authors.initials: P
authors.lastname: Goldstraw
authors.forename: Andrew
authors.initials: A
authors.lastname: Nicholson
authors.forename: Tsun Leung
authors.initials: TL
authors.lastname: Chan
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
authors.forename: Siu Tsan
authors.initials: ST
authors.lastname: Yuen
authors.forename: Suet Yi
authors.initials: SY
authors.lastname: Leung
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000595:Amino Acid Sequence; D018287:Carcinoma, Large Cell / Q000235:genetics; D003062:Codon / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D011905:Genes, ras / Q000235:genetics*; D006723:Hong Kong; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D008969:Molecular Sequence Data; D009367:Neoplasm Staging; D017354:Point Mutation / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D014481:United States
chemical_list: D003062:Codon; D004273:DNA, Neoplasm