Recurrent KRAS codon 146 mutations in human colorectal cancer.
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.
Edkins
Sarah
S
Cancer Genome Project, Welcome Trust Sanger Institute, Hinxton, UK.
O'Meara
Sarah
S
Parker
Adrian
A
Stevens
Claire
C
Reis
Marcelo
M
Jones
Siân
S
Greenman
Chris
C
Davies
Helen
H
Dalgliesh
Gillian
G
Forbes
Simon
S
Hunter
Chris
C
Smith
Raffaella
R
Stephens
Philip
P
Goldstraw
Peter
P
Nicholson
Andrew
A
Chan
Tsun Leung
TL
Velculescu
Victor E
VE
Yuen
Siu Tsan
ST
Leung
Suet Yi
SY
Stratton
Michael R
MR
Futreal
P Andrew
PA
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
D003062:Codon; D004273:DNA, Neoplasm