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| Status |
Public on Mar 11, 2011 |
| Title |
Mutated KRAS induces overexpression of DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase, in rectal carcinomas |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Mutations of the KRAS oncogene are predictive for resistance to treatment with antibodies against the epithelial growth factor receptor in patients with colorectal cancer. Overcoming this therapeutic dilemma could potentially be achieved by the introduction of drugs that inhibit signaling pathways that are activated by KRAS mutations. To comprehensively identify such signaling pathways we profiled pretreatment biopsies from 65 patients with locally advanced rectal cancer – 30 of which carried mutated KRAS - using global gene expression microarrays. By comparing all tumor tissues exclusively to matched normal mucosa, we could improve assay sensitivity, and identified a total of 22,297 features that were differentially expressed (adjusted p-value p<0.05) between normal mucosa and cancer, including several novel potential rectal cancer genes. We then used this comprehensive description of the rectal cancer transcriptome as the baseline for identifying KRAS-dependent alterations. The presence of activating KRAS mutations resulted in significant upregulation of 13 genes (adjusted p-value < 0.05), among them DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase. Inhibition of the expression of both genes has been achieved therapeutically with the MEK1-inhibitor PD98059 and the antibacterial compound Novobiocin, respectively, suggesting a potential approach to overcome resistance to treatment with antibodies against the epithelial growth factor receptor in patients with KRAS-mutant rectal carcinomas.
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| Overall design |
Paired samples of tumor and mucosa from a total of 65 patients, i.e. 130 arrays
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| Contributor(s) |
Gaedcke J, Grade M, Jung K, Camps J, Jo P, Emons G, Gehoff A, Sax U, Schirmer M, Becker H, Beissbarth T, Ried T, Ghadimi M |
| Citation(s) |
20725992 |
| Submission date |
Mar 11, 2010 |
| Last update date |
Feb 22, 2018 |
| Contact name |
Marian Grade |
| E-mail(s) |
marian.grade@gmail.com
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| Organization name |
University Medical Center Goettingen, Georg-August-University
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| Department |
Surgery
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| Street address |
Robert-Koch-Str. 40
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| City |
Goettingen |
| ZIP/Postal code |
37075 |
| Country |
Germany |
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| Platforms (1) |
| GPL4133 |
Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Feature Number version) |
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| Samples (130)
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| Relations |
| BioProject |
PRJNA124615 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE20842_RAW.tar |
1.1 Gb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
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