Recurrent KRAS codon 146 mutations in human colorectal cancer
Open accessAbstract
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.
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146 mutations do not alter the rate of GTP hydrolysis, but cause hyperactivation through an increased rate of GDP exchange.
“146 mutations do not alter the rate of GTP hydrolysis, but cause hyperactivation through an increased rate of GDP exchange4,10–12”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [11]
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- Authors
- Edkins, S., & O’Meara, S.
- Affiliations
- Wellcome Sanger Institute (GB)
- ORCID
- Edkins, S.
- Venue
- Cancer Biology & Therapy
- Publisher
- Informa UK Limited
- Published
- 2006-08-01
- Volume
- 5
- Issue
- 8
- Pages
- 928-932
- ISSN
- 1538-4047 (ISSN-L)
- PMC
- PMC2714972
- OpenAlex
- W1554963423
- Cited by
- 229
- References
- 23
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 6 · 2023: 7 · 2022: 9 · 2021: 17 · 2020: 10 · 2019: 9 · 2018: 11 · 2017: 8 · 2016: 8 · 2015: 13 · 2014: 22 · 2013: 19 · 2012: 26
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Biology & Therapy (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Funders
- Pew Charitable Trusts
- Wellcome Trust (077012)
- National Institutes of Health (5r01ca121113-15)
- National Cancer Institute (R01-CA121113, CA-121113, P50CA062924, CA062924)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- KRAS, colorectal cancer, somatic point mutations, oncogenic Ras, missense mutations, codon 61 mutation, colorectal cancer cell lines, lung adenocarcinoma, acute myeloid leukemia, B-cell acute lymphoblastic leukemia, mutation frequency
- MeSH terms
- Adenocarcinoma, Amino Acid Sequence, Codon, DNA Mutational Analysis, DNA, Neoplasm, Hong Kong, Humans, Molecular Sequence Data, Neoplasm Staging, Genes, ras, United States, Colorectal Neoplasms, Leukemia, Myeloid, Acute, Point Mutation, Sequence Homology, Amino Acid, Carcinoma, Large Cell, Precursor Cell Lymphoblastic Leukemia-Lymphoma
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