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

• Published in: Molecular cancer therapeutics 2008-09, Vol.7 (9), p.3038-3046
• Main Authors: Huang, R Stephanie, Duan, Shiwei, Kistner, Emily O, Hartford, Christine M, Dolan, M Eileen
• Format: Article
• Language: English
• Subjects: African Continental Ancestry Group - genetics; carboplatin; Carboplatin - pharmacology; Cell Death - drug effects; Cell Line; Cell Proliferation - drug effects; Cell Survival - drug effects; cytotoxicity; gene expression; Gene Expression Regulation - drug effects; Genetic Variation - drug effects; Genotype; Glypicans - genetics; HapMap Yoruban; Humans; Linkage Disequilibrium - genetics; Mitogen-Activated Protein Kinase 1 - genetics; pharmacogenomics; Polymorphism, Single Nucleotide - genetics; Proto-Oncogene Proteins B-raf - genetics; Regression Analysis
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-08-0248

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 IC 50 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. [Mol Cancer Ther 2008;7(9):3038–46]