Genomic and Biological Characterization of Exon 4 KRAS Mutations in Human Cancer

Janakiraman, Manickam; Vakiani, Efsevia; Zeng, Zhaoshi; Pratilas, Christine A.; Taylor, Barry S.; Chitale, Dhananjay; Halilovic, Ensar; Wilson, Manda; Huberman, Kety; Ricarte Filho, Julio Cezar; Persaud, Yogindra; Levine, Douglas A.; Fagin, James A.; Jhanwar, Suresh C.; Mariadason, John M.; Lash, Alex; Ladanyi, Marc; Saltz, Leonard B.; Heguy, Adriana; Paty, Philip B.; Solit, David B.

doi:10.1158/0008-5472.can-10-0192

Cited by 290Protein Kinase Regulation and GTPase SignalingColorectal Cancer Treatments and StudiesCancer Genomics and Diagnostics

Genomic and Biological Characterization of Exon 4 KRAS Mutations in Human Cancer

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Janakiraman, Manickam, Vakiani, Efsevia, Zeng, Zhaoshi, Pratilas, Christine A., Taylor, Barry S., Chitale, Dhananjay, Halilovic, Ensar, Wilson, Manda +13 more·2010·Cancer Research

DOI 10.1158/0008-5472.can-10-0192PMC PMC2943514

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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 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 [12]

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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: Janakiraman, Manickam
Vakiani, Efsevia
Pratilas, Christine A.
Taylor, Barry S.
Chitale, Dhananjay
Halilovic, Ensar
Wilson, Manda
Huberman, Kety
Persaud, Yogindra
Levine, Douglas A.
Fagin, James A.
Mariadason, John M.
Lash, Alex
Ladanyi, Marc
Saltz, Leonard B.
Heguy, Adriana
Paty, Philip B.
Solit, David B.
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2010-07-14
Volume: 70
Issue: 14
Pages: 5901-5911
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-10-0192
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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