Mapping genes that contribute to daunorubicin-induced cytotoxicity.

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 mumol/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 < or = 2.0 x 10(-4), false discovery rate < or = 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.

• Authors: Shiwei Duan, Wasim K Bleibel, Rong Stephanie Huang, Sunita J Shukla, Xiaolin Wu, Judith A Badner, M Eileen Dolan
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 11 Pg. 5425-33 (Jun 01 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17545624 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibiotics, Antineoplastic
• Daunorubicin

Topics

• Antibiotics, Antineoplastic (pharmacology)
• Cell Line, Tumor
• Chromosome Mapping
• Daunorubicin (pharmacology)
• Genetic Linkage
• Genome, Human
• Humans
• Lymphocytes (drug effects, physiology)
• Polymorphism, Single Nucleotide