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Gemcitabine and arabinosylcytosin pharmacogenomics: genome-wide association and drug response biomarkers
- Source :
- PLoS ONE, Vol 4, Iss 11, p e7765 (2009), PLoS ONE
- Publication Year :
- 2009
- Publisher :
- Public Library of Science (PLoS), 2009.
-
Abstract
- Cancer patients show large individual variation in their response to chemotherapeutic agents. Gemcitabine (dFdC) and AraC, two cytidine analogues, have shown significant activity against a variety of tumors. We previously used expression data from a lymphoblastoid cell line-based model system to identify genes that might be important for the two drug cytotoxicity. In the present study, we used that same model system to perform a genome-wide association (GWA) study to test the hypothesis that common genetic variation might influence both gene expression and response to the two drugs. Specifically, genome-wide single nucleotide polymorphisms (SNPs) and mRNA expression data were obtained using the Illumina 550K(R) HumanHap550 SNP Chip and Affymetrix U133 Plus 2.0 GeneChip, respectively, for 174 ethnically-defined "Human Variation Panel" lymphoblastoid cell lines. Gemcitabine and AraC cytotoxicity assays were performed to obtain IC(50) values for the cell lines. We then performed GWA studies with SNPs, gene expression and IC(50) of these two drugs. This approach identified SNPs that were associated with gemcitabine or AraC IC(50) values and with the expression regulation for 29 genes or 30 genes, respectively. One SNP in IQGAP2 (rs3797418) was significantly associated with variation in both the expression of multiple genes and gemcitabine and AraC IC(50). A second SNP in TGM3 (rs6082527) was also significantly associated with multiple gene expression and gemcitabine IC50. To confirm the association results, we performed siRNA knock down of selected genes with expression that was associated with rs3797418 and rs6082527 in tumor cell and the knock down altered gemcitabine or AraC sensitivity, confirming our association study results. These results suggest that the application of GWA approaches using cell-based model systems, when combined with complementary functional validation, can provide insights into mechanisms responsible for variation in cytidine analogue response.
- Subjects :
- Antimetabolites, Antineoplastic
medicine.medical_specialty
lcsh:Medicine
Genome-wide association study
Single-nucleotide polymorphism
Biology
Deoxycytidine
Polymorphism, Single Nucleotide
Linkage Disequilibrium
Inhibitory Concentration 50
03 medical and health sciences
0302 clinical medicine
Neoplasms
Molecular genetics
Ethnicity
medicine
Humans
RNA, Messenger
lcsh:Science
Oligonucleotide Array Sequence Analysis
030304 developmental biology
Pharmacology
Regulation of gene expression
Genetics
0303 health sciences
Multidisciplinary
Genetics and Genomics/Functional Genomics
lcsh:R
Cytarabine
Genetic Variation
Genetics and Genomics
Gemcitabine
3. Good health
SNP genotyping
Pharmacogenetics
030220 oncology & carcinogenesis
Pharmacogenomics
Cancer research
Gene chip analysis
lcsh:Q
Pharmacology/Personalized Medicine
Biomarkers
Research Article
Genome-Wide Association Study
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 4
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....27d70d3e9af94c7954378924cd30c800