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Genomic and Biological Characterization of Exon 4 KRAS Mutations in Human Cancer
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Abstract
Mutations in RAS proteins occur widely in human cancer. Prompted by the confirmation of KRAS mutation as a predictive biomarker of response to epidermal growth factor receptor (EGFR)–targeted therapies, limited clinical testing for RAS pathway mutations has recently been adopted. We performed a multiplatform genomic analysis to characterize, in a nonbiased manner, the biological, biochemical, and prognostic significance of Ras pathway alterations in colorectal tumors and other solid tumor malignancies. Mutations in exon 4 of KRAS were found to occur commonly and to predict for a more favorable clinical outcome in patients with colorectal cancer. Exon 4 KRAS mutations, all of which were identified at amino acid residues K117 and A146, were associated with lower levels of GTP-bound RAS in isogenic models. These same mutations were also often accompanied by conversion to homozygosity and increased gene copy number, in human tumors and tumor cell lines. Models harboring exon 4 KRAS mutations exhibited mitogen-activated protein/extracellular signal-regulated kinase kinase dependence and resistance to EGFR-targeted agents. Our findings suggest that RAS mutation is not a binary variable in tumors, and that the diversity in mutant alleles and variability in gene copy number may also contribute to the heterogeneity of clinical outcomes observed in cancer patients. These results also provide a rationale for broader KRAS testing beyond the most common hotspot alleles in exons 2 and 3. Cancer Res; 70(14); 5901–11. ©2010 AACR.
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“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 [12]
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Metadata
- Authors
- Janakiraman, M., Vakiani, E., Zeng, Z., Pratilas, C. A., Taylor, B. S., Chitale, D., Halilovic, E., Wilson, M., Huberman, K., Ricarte Filho, J. C., Persaud, Y., Levine, D. A., Fagin, J. A., Jhanwar, S. C., Mariadason, J. M., Lash, A., Ladanyi, M., Saltz, L. B., Heguy, A., Paty, P. B., & Solit, D. B.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Authors' Affiliations: 1Human Oncology and Pathogenesis Program and the Departments of 2Pathology, 3Surgery, 4Pediatrics, 5Computational Biology, 6Molecular Pharmacology and Chemistry, and 7Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; and 8The Ludwig Institute for Cancer Research, Melbourne, Australia
- ORCID
- Venue
- Cancer Research
- Published
- 2010-07-14
- Volume
- 70
- Issue
- 14
- Pages
- 5901-5911
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2943514
- OpenAlex
- W2125592514
- Cited by
- 290
- References
- 53
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 14 · 2023: 14 · 2022: 11 · 2021: 11 · 2020: 15 · 2019: 18 · 2018: 18 · 2017: 21 · 2016: 22 · 2015: 35 · 2014: 34 · 2013: 23 · 2012: 16
- FWCI
- 8.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA127240, P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- colorectal cancer, anti-EGFR therapy resistance, predictive biomarkers, gene copy number, prognostic value, solid tumors, KRAS testing
- MeSH terms
- Adenocarcinoma, Animals, Benzamides, Diphenylamine, Exons, Genotype, Humans, Mice, Inbred BALB C, Mice, Nude, Mutation, Proto-Oncogene Proteins, Genes, ras, Mass Spectrometry, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Mutagenesis, Site-Directed, ras Proteins, Mitogen-Activated Protein Kinases, Cell Line, Tumor, Mice, Comparative Genomic Hybridization, ErbB Receptors
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