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Radiation pharmacogenomics: a genome-wide association approach to identify radiation response biomarkers using human lymphoblastoid cell lines.

ABSTRACT: Radiation therapy is used to treat half of all cancer patients. Response to radiation therapy varies widely among patients. Therefore, we performed a genome-wide association study (GWAS) to identify biomarkers to help predict radiation response using 277 ethnically defined human lymphoblastoid cell lines (LCLs). Basal gene expression levels and 1.3 million genome-wide single nucleotide polymorphism (SNP) markers from both Affymetrix and Illumina platforms were assayed for all 277 human LCLs. MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assays for radiation cytotoxicity were also performed to obtain area under the curve (AUC) as a radiation response phenotype for use in the association studies. Functional validation of candidate genes, selected from an integrated analysis that used SNP, expression, and AUC data, was performed with multiple cancer cell lines using specific siRNA knockdown, followed by MTS and colony-forming assays. A total of 27 loci, each containing at least two SNPs within 50 kb with P-values less than 10(-4) were associated with radiation AUC. A total of 270 expression probe sets were associated with radiation AUC with P < 10(-3). The integrated analysis identified 50 SNPs in 14 of the 27 loci that were associated with both AUC and the expression of 39 genes, which were also associated with radiation AUC (P < 10(-3)). Functional validation using siRNA knockdown in multiple tumor cell lines showed that C13orf34, MAD2L1, PLK4, TPD52, and DEPDC1B each significantly altered radiation sensitivity in at least two cancer cell lines. Studies performed with LCLs can help to identify novel biomarkers that might contribute to variation in response to radiation therapy and enhance our understanding of mechanisms underlying that variation.

SUBMITTER: Niu N

PROVIDER: S-EPMC2963812 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Radiation pharmacogenomics: a genome-wide association approach to identify radiation response biomarkers using human lymphoblastoid cell lines.

Niu Nifang N Qin Yuxin Y Fridley Brooke L BL Hou Junmei J Kalari Krishna R KR Zhu Minjia M Wu Tse-Yu TY Jenkins Gregory D GD Batzler Anthony A Wang Liewei L

Genome research 20101005 11

Radiation therapy is used to treat half of all cancer patients. Response to radiation therapy varies widely among patients. Therefore, we performed a genome-wide association study (GWAS) to identify biomarkers to help predict radiation response using 277 ethnically defined human lymphoblastoid cell lines (LCLs). Basal gene expression levels and 1.3 million genome-wide single nucleotide polymorphism (SNP) markers from both Affymetrix and Illumina platforms were assayed for all 277 human LCLs. MTS ...[more]

PMID: 20923822

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Project description: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.

Dataset Information

Radiation pharmacogenomics: a genome-wide association approach to identify radiation response biomarkers using human lymphoblastoid cell lines.

Publications

Radiation pharmacogenomics: a genome-wide association approach to identify radiation response biomarkers using human lymphoblastoid cell lines.

Similar Datasets

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