Impact of combinations of single-nucleotide polymorphisms of anthracycline transporter genes upon the efficacy and toxicity of induction chemotherapy in acute myeloid leukemia

Abstract

Anthracycline uptake could be affected by influx and efflux transporters in acute myeloid leukemia (AML). Combinations of single-nucleotide polymorphisms (SNPs) of wild-type genotype of influx transporters (SLC22A16, SLCO1B1) and homozygous variant genotypes of ABC polymorphisms (ABCB1, ABCC1, ABCC2, ABCG2) were evaluated in 225 adult de novo AML patients. No differences in complete remission were reported, but higher induction death was observed with combinations of SLCO1B1 rs4149056 and ABCB1 (triple variant haplotype, rs1128503), previously associated with ABCB1 and SLCO1B1 SNPs. Several combinations of SLCO1B1 and SLC22A16 with ABCB1 SNPs were associated with higher toxicities, including nephrotoxicity and hepatotoxicity, neutropenia, previously related to ABCB1, and a novel correlation with mucositis. Combination of SLC22A16 rs714368 and ABCG2 rs2231142 was related to cardiac toxicity, reproducing previous correlations with ABCG2. This study shows the impact of transporter polymorphisms in AML chemotherapy safety. Further prospective studies with larger populations are needed to validate these associations.

Keywords:

• SLCO1B1
• ABCB1
• polymorphism
• anthracyclines
• idarubicin
• SNP-SNP combination

Acknowledgements

The authors are grateful to Dr. E. Busó from SCSIE (Universidad de Valencia) for his work and help with Mass Array Sequenom^® genotyping, and Dr. D. Hervás from Unidad de Bioestadística (Instituto Investigación Sanatoria La Fe) for Biostatistical facilities.

Author contributions

JEMV and PM contributed equally as first authors. They contributed to the design of the study, data collection and data analysis, and writing of the manuscript. DMC, MJH, RRV were involved in the data collection and data interpretation, data analysis, and critical revision of the manuscript. JC contributed to the sampling process and genotyping experiments. ASA, BB, OBL, IC, EAC, RRV and JS were participated in data collection. MAS and JLP was involved in the design of the study, sample process, administrative support as well as critical revision of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was supported by grants from the “Instituto Carlos III” [grant number PIE13/00046] and the “Instituto Investigación Sanitaria La Fe” [grant number 2013/0331] assigned to the Pharmacy and Hematology Departments and the Pharmacogenetics Unit of the “Instituto Investigación Sanitaria La Fe” and the “Área del Medicamento” of the “Hospital Universitari i Politècnic La Fe”, Valencia, Spain. Besides, in part this work was supported by research funding from FEDER funds [grant number CIBERONC (CB16/12/00284)]. The study was performed on behalf of the PETHEMA cooperative group and IIS La Fe. Samples have been managed by the La Fe Biobank, licensed as required by Spanish Royal Decree 1716/2011 of 18 November [grant number PT17/0015/0043].