Mapping genes that contribute to daunorubicin-induced cytotoxicity

Shiwei Duan, Wasim K. Bleibel, Rong Stephanie Huang, Sunita J. Shukla, Xiaolin Wu, Judith A. Badner, M. Eileen Dolan

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

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 IC 50, 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 × 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.

Original languageEnglish (US)
Pages (from-to)5425-5433
Number of pages9
JournalCancer Research
Volume67
Issue number11
DOIs
StatePublished - Jun 1 2007

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    Duan, S., Bleibel, W. K., Huang, R. S., Shukla, S. J., Wu, X., Badner, J. A., & Dolan, M. E. (2007). Mapping genes that contribute to daunorubicin-induced cytotoxicity. Cancer Research, 67(11), 5425-5433. https://doi.org/10.1158/0008-5472.CAN-06-4431