Genetic Variants of ABC and SLC Transporter Genes and Chronic Myeloid Leukaemia: Impact on Susceptibility and Prognosis

Abstract

Solute carrier (SLC) and ATP-binding cassette (ABC) transporters comprise a variety of proteins expressed on cell membranes responsible for intrusion or extrusion of substrates, respectively, including nutrients, xenobiotics, and chemotherapeutic agents. These transporters mediate the cellular disposition of tyrosine kinase inhibitors (TKIs), and their genetic variants could affect its function, potentially predisposing patients to chronic myeloid leukaemia (CML) and modulating treatment response. We explored the impact of genetic variability (single nucleotide variants-SNVs) of drug transporter genes (ABCB1, ABCG2, SLC22A1, and SLC22A5) on CML susceptibility, drug response, and BCR-ABL1 mutation status. We genotyped 10 SNVs by tetra-primers-AMRS-PCR in 198 CML patients and 404 controls, and assessed their role in CML susceptibility and prognosis. We identified five SNVs associated with CML predisposition, with some variants increasing disease risk, including TT genotype ABCB1 (rs1045642), and others showing a protective effect (GG genotype SLC22A5 rs274558). We also observed different haplotypes and genotypic profiles associated with CML predisposition. Relating to drug response impact, we found that CML patients with the CC genotype (rs2231142 ABCG2) had an increased risk of TKI resistance (six-fold). Additionally, CML patients carrying the CG genotype (rs683369 SLC22A1) presented a 4.54-fold higher risk of BCR-ABL1 mutations. Our results suggest that drug transporters' SNVs might be involved in CML susceptibility and TKI response, and predict the risk of BCR-ABL1 mutations, highlighting the impact that SNVs could have in therapeutic selection.

Keywords: CML; TKI resistance; cancer predisposition; drug transporters.

Figure 1

Haplotypes (H) and genotypic profiles (GP) significantly correlated with CML development; (a) the haplotypes and (b) the GPs positively correlated with CML susceptibility. The respective p value is shown for each analysis. Haplotype groups: ABCB1: rs1045642/rs1128503/rs2032582; ABCG2: rs2231142/rs2231137; SLC22A1: rs628031/rs683369/rs1867351; SLC22A5: rs274558/rs2631365. Genotypic profile categories: Efflux (ABCB1: rs1045642/rs1128503/rs2032582/ABCG2: rs2231142/rs2231137); Influx (SLC22A1: rs628031/rs683369/rs1867351/SLC22A5: rs274558/rs2631365); ABCB1: rs1045642/rs1128503/rs2032582; ABCG2: rs2231142/rs2231137; SLC22A5: rs274558/rs2631365; Genotypic Significant (ABCB1: rs1045642/rs1128503/ABCG2: rs2231142/SLC22A5: rs274558/rs2631365).

Figure 2

Prognostic impact of SNVs in influx and efflux transporters genes in CML patients. In (a) are the alleles, genotypes, haplotypes (H), and genotypic profiles (GP) significantly associated with TKI response in CML patients; (b) depicts the time to TKI change in CML patients according to ABCG2 (rs2231142) genotypes. This analysis was performed by the Kaplan Meier–method, differences in survival were tested with the log-rank test, and hazard ratios (HR) with 95% confidence interval (CI) were calculated using the Cox proportional hazard model. In (c) are the alleles, genotypes, haplotypes, and GPs significantly associated with the number of TKIs needed by CML-resistant patients. In (d) are the alleles, genotype, haplotypes and GPs significantly associated with BCR-ABL1 mutations in CML patients. The respective p value is shown for each analysis. Haplotypes groups: ABCG2: rs2231142/rs2231137; SLC22A1: rs628031/rs683369/rs1867351; SLC22A5: rs274558/rs2631365. Genotypic profile categories: Efflux (ABCB1: rs1045642/rs1128503/rs2032582/ABCG2: rs2231142/rs2231137); Influx (SLC22A1: rs628031/rs683369/rs1867351/SLC22A5: rs274558/rs2631365); ABCB1: rs1045642/rs1128503/rs2032582; ABCG2: rs2231142/rs2231137; SLC22A1: rs628031/rs683369/rs1867351. MD—model dominant; MR—model recessive; MOD—model overdominant; MCD—model co-dominant.