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

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 14; pp. 5901 - 5911
• Main Authors: JANAKIRAMAN, Manickam, VAKIANI, Efsevia, 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, ZHAOSHI ZENG, SOLIT, David B, PRATILAS, Christine A, TAYLOR, Barry S, CHITALE, Dhananjay, HALILOVIC, Ensar, WILSON, Manda, HUBERMAN, Kety, RICARTE, Julio Cezar
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-07-2010
• Subjects: Adenocarcinoma - enzymology; Adenocarcinoma - genetics; Animals; Antineoplastic agents; Benzamides - pharmacology; Biological and medical sciences; Cell Line, Tumor; Colorectal Neoplasms - enzymology; Colorectal Neoplasms - genetics; Comparative Genomic Hybridization; Diphenylamine - analogs & derivatives; Diphenylamine - pharmacology; Exons; Genes, ras; Genotype; Humans; Mass Spectrometry; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinases - metabolism; Mutagenesis, Site-Directed; Mutation; Pharmacology. Drug treatments; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - biosynthesis; ras Proteins - genetics; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Tumors; Characterization; K ras Gene; Human; Exon; C-Onc gene; Genomics; Genetics; Mutation; Malignant tumor; Genome; Protooncogene; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-0192

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.