Genetic variants associated with carboplatin-induced cytotoxicity in cell lines derived from Africans - PubMed (original) (raw)

Genetic variants associated with carboplatin-induced cytotoxicity in cell lines derived from Africans

R Stephanie Huang et al. Mol Cancer Ther. 2008 Sep.

Abstract

To gain a better understanding of the genetic variants associated with carboplatin-induced cytotoxicity in individuals of African descent, we present a step-wise approach integrating genotypes, gene expression, and sensitivity of HapMap cell lines to carboplatin. Cell lines derived from 30 trios of African descent (YRI) were used to develop a preclinical model to identify genetic variants and gene expression that contribute to carboplatin-induced cytotoxicity. Cytotoxicity was determined as cell growth inhibition at increasing concentrations of carboplatin for 72 h. Gene expression of 89 HapMap YRI cell lines was determined using the Affymetrix GeneChip Human Exon 1.0 ST Array. Single nucleotide polymorphism genotype and the percent survival at different treatment concentrations along with carboplatin IC50 were linked through whole genome association. A second association test was done between single nucleotide polymorphism genotype and gene expression, and linear regression was then used to capture those genes whose expression correlated to drug sensitivity phenotypes. This approach allows us to identify genetic variants that significantly associate with sensitivity to the cytotoxic effects of carboplatin through their effect on gene expression. We found a gene (GPC5) whose expression is important in all carboplatin treatment concentrations as well as many genes unique to either low (e.g., MAPK1) or high (e.g., BRAF, MYC, and BCL2L1) concentrations of drug. Our whole genome approach enables us to evaluate the contribution of genetic and gene expression variation to a wide range of cellular phenotypes. The identification of concentration specific genetic signatures allows for potential integration of pharmacokinetics, pharmacodynamics, and pharmacogenetics in tailoring chemotherapy.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

Dr. Dolan has presented seminars at Affymetrix funded meetings. The other authors reported no potential conflicts of interest.

Figures

Figure 1

Figure 1. Relationship between rs1031324, GPC5 gene expression, and carboplatin IC50 in the YRI samples

A, rs1031324 genotype and log2-transformed carboplatin IC50 association. B, rs1031324 genotype and log2-transformed GPC5 expression association. C, log2-transformed GPC5 expression and log2-transformed carboplatin IC50 correlation.

Figure 2

Figure 2. Relationship between rs3821666, MAPK1 gene expression, and percent survival after 10 µmol/L carboplatin treatment in the YRI samples

A, rs3821666 genotype and log2-transformed percent survival after 10 µmol/L carboplatin treatment association. B, rs3821666 genotype and log2-transformed MAPK1 expression association. C, log2-transformed MAPK1 expression and log2-transformed percent survival after 10 µmol/L carboplatin treatment correlation.

Figure 3

Figure 3. Relationship between rs11993726, BRAF gene expression, and percent survival after 40 µmol/L carboplatin treatment in the YRI samples

A, rs11993726 genotype and log2-transformed percent survival after 40 µmol/L carboplatin treatment association. B, rs11993726 genotype and log2-transformed BRAF expression association. C, log2-transformed BRAF expression and log2-transformed percent survival after 40 µmol/L carboplatin treatment correlation.

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