title: Genomic and biological characterization of exon 4 KRAS mutations in human cancer.
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.
authors.affiliation: Departments of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Manickam
authors.initials: M
authors.lastname: Janakiraman
authors.forename: Efsevia
authors.initials: E
authors.lastname: Vakiani
authors.forename: Zhaoshi
authors.initials: Z
authors.lastname: Zeng
authors.forename: Christine A
authors.initials: CA
authors.lastname: Pratilas
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Chitale
authors.forename: Ensar
authors.initials: E
authors.lastname: Halilovic
authors.forename: Manda
authors.initials: M
authors.lastname: Wilson
authors.forename: Kety
authors.initials: K
authors.lastname: Huberman
authors.forename: Julio Cezar
authors.initials: JC
authors.lastname: Ricarte Filho
authors.forename: Yogindra
authors.initials: Y
authors.lastname: Persaud
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Levine
authors.forename: James A
authors.initials: JA
authors.lastname: Fagin
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Jhanwar
authors.forename: John M
authors.initials: JM
authors.lastname: Mariadason
authors.forename: Alex
authors.initials: A
authors.lastname: Lash
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Saltz
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: Philip B
authors.initials: PB
authors.lastname: Paty
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005091:Exons; D011905:Genes, ras; D005838:Genotype; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D001549:Benzamides; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C506614:mirdametinib; D004159:Diphenylamine; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins