Genomic and biological characterization of exon 4 KRAS mutations in human cancer Journal Article

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.
Article 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. ©2010 AACR.
Keywords: mitogen activated protein kinase; controlled study; protein expression; gene mutation; human cell; major clinical study; exon; mutation; exons; proto-oncogene proteins; nonhuman; solid tumor; genetic analysis; adenocarcinoma; mass spectrometry; mouse; animals; mice; allele; animal experiment; animal model; genetic variability; genotype; receptor, epidermal growth factor; cell line, tumor; cetuximab; mice, inbred balb c; colorectal neoplasms; homozygosity; mice, nude; colorectal tumor; tumor cell line; gefitinib; mutagenesis, site-directed; ras proteins; gene dosage; genes, ras; k ras protein; mitogen-activated protein kinases; guanosine triphosphate; comparative genomic hybridization; n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide; benzamides; diphenylamine
Journal Title: Cancer Research
Volume: 70
Issue: 14
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2010-07-15
Start Page: 5901
End Page: 5911
Language: English
DOI: 10.1158/0008-5472.can-10-0192
PUBMED: 20570890
PROVIDER: scopus
PMCID: PMC2943514
Notes: --- - "Cited By (since 1996): 7" - "Export Date: 20 April 2011" - "CODEN: CNREA" - "Source: Scopus"
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MSK Authors
  1. James A Fagin
    109 Fagin
  2. Adriana Heguy
    85 Heguy
  3. Leonard B Saltz
    599 Saltz
  4. Philip B Paty
    373 Paty
  5. David Solit
    440 Solit
  6. Douglas A Levine
    356 Levine
  7. Dhananjay Arun Chitale
    33 Chitale
  8. Zhaoshi Zeng
    84 Zeng
  9. Marc Ladanyi
    879 Ladanyi
  10. Alex E Lash
    24 Lash
  11. Efsevia Vakiani
    164 Vakiani
  12. Suresh C Jhanwar
    217 Jhanwar
  13. Barry Stephen Taylor
    144 Taylor
  14. Yogindra Paul Persaud
    14 Persaud
  15. Manda E Wilson
    5 Wilson