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Mapping Genes that Contribute to Daunorubicin-Induced Cytotoxicity

Departments of ¹ Medicine, ² Human Genetics, and ³ Psychiatry, The University of Chicago, Chicago, Illinois

Requests for reprints: M. Eileen Dolan, Department of Medicine, University of Chicago, 5841 S. Maryland Avenue, Box MC2115, Chicago, IL 60637. Phone: 773-702-4441; Fax: 773-702-0963; E-mail: edolan{at}medicine.bsd.uchicago.edu.

Daunorubicin is an anthracycline antibiotic agent used in the treatment of hematopoietic malignancies. Toxicities associated with this agent include myelosuppression and cardiotoxicity; however, the genes or genetic determinants that contribute to these toxicities are unknown. We present an unbiased genome-wide approach that incorporates heritability, whole-genome linkage analysis, and linkage-directed association to uncover genetic variants contributing to the sensitivity to daunorubicin-induced cytotoxicity. Cell growth inhibition in 324 Centre d' Etude du Polymorphisme Humain lymphoblastoid cell lines (24 pedigrees) was evaluated following treatment with daunorubicin for 72 h. Heritability analysis showed a significant genetic component contributing to the cytotoxic phenotypes (h² = 0.18–0.63 at 0.0125, 0.025, 0.05, 0.1, 0.2, and 1.0 µmol/L daunorubicin and at the IC₅₀, the dose required to inhibit 50% cell growth). Whole-genome linkage scans at all drug concentrations and IC₅₀ uncovered 11 regions with moderate peak LOD scores (>1.5), including 4q28.2 to 4q32.3 with a maximum LOD score of 3.18. The quantitative transmission disequilibrium tests were done using 31,312 high-frequency single-nucleotide polymorphisms (SNP) located in the 1 LOD confidence interval of these 11 regions. Thirty genes were identified as significantly associated with daunorubicin-induced cytotoxicity (P 2.0 x 10^–4, false discovery rate 0.1). Pathway and functional gene ontology analysis showed that these genes were overrepresented in the phosphatidylinositol signaling system, axon guidance pathway, and GPI-anchored proteins family. Our findings suggest that a proportion of susceptibility to daunorubicin-induced cytotoxicity may be controlled by genetic determinants and that analysis using linkage-directed association studies with dense SNP markers can be used to identify the genetic variants contributing to cytotoxicity. [Cancer Res 2007;67(11):5425–33]

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				R. S. Huang, S. Duan, E. O. Kistner, W. K. Bleibel, S. M. Delaney, D. L. Fackenthal, S. Das, and M. E. Dolan Genetic Variants Contributing to Daunorubicin-Induced Cytotoxicity Cancer Res., May 1, 2008; 68(9): 3161 - 3168. [Abstract] [Full Text] [PDF]