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Genome‐wide approach to finding determinants of susceptibility to chemotherapeutic agents
Author(s) -
Shukla S.,
Badner J.,
Cheng C.,
Bleibel W.,
Dolan M. E.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.11.018
Subject(s) - cisplatin , candidate gene , carboplatin , gene , biology , pedigree chart , genetic linkage , genetics , microarray analysis techniques , chromosome , computational biology , pharmacology , gene expression , chemotherapy
Background Our aim was to identify candidate genes and genetic variants involved in cellular susceptibility to chemotherapeutic agents without a priori assumptions about the genes. To date, research has focused on known candidate genes involved in pharmacokinetic and pharmacodynamic pathways for specific chemotherapy. Methods Three‐generation CEPH pedigrees were used to evaluate the genetic contribution to cellular growth inhibition by exposing the cells to increasing concentrations of cisplatin for 48 hours or carboplatin for 72 hours. Results The heritability of cisplatin‐ and carboplatin‐induced cytotoxicity was found to be between 0.38–0.47 (p<0.0001) and 0.36–1.0 (p<0.02), respectively. The most significant findings from linkage analysis for cisplatin were on chromosome 1 at 44 cM in variance components analysis and chromosome 12 at 147 cM in nonparametric linkage analysis. Candidate genes within a 1‐lod confidence interval surrounding the peaks on chromosome 1 (188 genes) and 12 (106 genes) included CASP9, SFN, STMN1, UBC, POLE and ZNF84 . Using expression array, we compared gene expression differences at baseline and changes over time following treatment with cisplatin. Genes common to linkage analysis and expression array included ZNF84, RERE, NPPB , and SFRS8 . Conclusions These data show the power of using large, extensively genotyped pedigrees with microarray analysis for evaluating the genetic contribution to sensitivity of cell growth inhibition by anticancer agents. Clinical Pharmacology & Therapeutics (2005) 77 , P4–P4; doi: 10.1016/j.clpt.2004.11.018