Genetic variants contributing to daunorubicin-induced cytotoxicity.

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Huang RS, Duan S, Kistner EO, Bleibel WK, Delaney SM, Fackenthal DL, Das S, Dolan ME

Genetic variants contributing to daunorubicin-induced cytotoxicity.

Cancer Res. 2008 May 1;68(9):3161-8. doi: 10.1158/0008-5472.CAN-07-6381.

PubMed ID

18451141 [ View in PubMed

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Abstract

Identifying heritable genetic variants responsible for chemotherapeutic toxicities has been challenging due in part to its multigenic nature. To date, there is a paucity of data on genetic variants associated with patients experiencing severe myelosuppression or cardiac toxicity following treatment with daunorubicin. We present a genome-wide model using International HapMap cell lines that integrate genotype and gene expression to identify genetic variants that contribute to daunorubicin-induced cytotoxicity. A cell growth inhibition assay was used to measure variations in the cytotoxicity of daunorubicin. Gene expression was determined using the Affymetrix GeneChip Human Exon 1.0ST Array. Using sequential analysis, we evaluated the associations between genotype and cytotoxicity, those significant genotypes with gene expression and correlated gene expression of the identified candidates with cytotoxicity. A total of 26, 9, and 18 genetic variants were identified to contribute to daunorubicin-induced cytotoxicity through their effect on 16, 9, and 36 gene expressions in the combined, Centre d' Etude du Polymorphisme Humain (CEPH), and Yoruban populations, respectively. Using 50 non-HapMap CEPH cell lines, single nucleotide polymorphisms generated through our model predicted 29% of the overall variation in daunorubicin sensitivity and the expression of CYP1B1 was significantly correlated with sensitivity to daunorubicin. In the CEPH validation set, rs120525235 and rs3750518 were significant predictors of transformed daunorubicin IC(50) (P = 0.005 and P = 0.0008, respectively), and rs1551315 trends toward significance (P = 0.089). This unbiased method can be used to elucidate genetic variants contributing to a wide range of cellular phenotypes.

DrugBank Data that Cites this Article

Pharmaco-genomics

Drug	Interacting Gene/Enzyme	Allele name	Genotypes	Defining change(s)	Type(s)	Description	Details
Daunorubicin	Cytochrome P450 1B1 Gene symbol: CYP1B1 UniProt: Q16678	---	(G;G) / (C;G)	G allele (rs10932125)	ADR Directly Studied	The presence of this genotype in CYP1B1 may be associated with an increased risk of drug-induced cytotoxicity from daunorubicin therapy.	Details
Daunorubicin	Heterogeneous nuclear ribonucleoprotein D0 Gene symbol: HNRNPD UniProt: Q14103	---	(A;A) / (A;G)	A allele (rs3750518)	ADR Directly Studied	The presence of this genotype in HNRNPD may be associated with an increased risk of drug-induced cytotoxicity from daunorubicin therapy.	Details
Daunorubicin	SEC14-like protein 3 Gene symbol: SEC14L3 UniProt: Q9UDX4	---	(T;T) / (G;T)	T allele (rs6603859)	ADR Directly Studied	The presence of this genotype in SEC14L3 may be associated with an increased risk of drug-induced cytotoxicity from daunorubicin therapy.	Details
Daunorubicin	Inhibitor of nuclear factor kappa-B kinase subunit epsilon Gene symbol: IKBKE UniProt: Q14164	---	(A;A) / (A;G)	A allele (rs7929521)	ADR Directly Studied	The presence of this genotype in IKBKE may be associated with an increased risk of drug-induced cytotoxicity from daunorubicin therapy.	Details