Associations of genetic polymorphisms of the transporters organic cation transporter 2 (OCT2), multidrug and toxin extrusion 1 (MATE1), and ATP-binding cassette subfamily C member 2 (ABCC2) with platinum-based chemotherapy response and toxicity in non-small cell lung cancer patients

Abstract

BackgroundPlatinum-based chemotherapy is the first-line treatment of non-small cell lung cancer (NSCLC); it is therefore important to discover biomarkers that can be used to predict the efficacy and toxicity of this treatment. Four important transporter genes are expressed in the kidney, including organic cation transporter 2 (OCT2), multidrug and toxin extrusion 1 (MATE1), ATP-binding cassette subfamily B member 1 (ABCB1), and ATP-binding cassette subfamily C member 2 (ABCC2), and genetic polymorphisms in these genes may alter the efficacy and adverse effects of platinum drugs. This study aimed to evaluate the association of genetic polymorphisms of these transporters with platinum-based chemotherapy response and toxicity in NSCLC patients.MethodsA total of 403 Chinese NSCLC patients were recruited for this study. All patients were newly diagnosed with NSCLC and received at least two cycles of platinum-based chemotherapy. The tumor response and toxicity were evaluated after two cycles of treatment, and the patients’ genomic DNA was extracted. Seven single-nucleotide polymorphisms in four transporter genes were selected to investigate their associations with platinum-based chemotherapy toxicity and response.ResultsOCT2 rs316019 was associated with hepatotoxicity (P = 0.026) and hematological toxicity (P = 0.039), and MATE1 rs2289669 was associated with hematological toxicity induced by platinum (P = 0.016). In addition, ABCC2 rs717620 was significantly associated with the platinum-based chemotherapy response (P = 0.031). ABCB1 polymorphisms were associated with neither response nor toxicity.ConclusionOCT2 rs316019, MATE1 rs2289669, and ABCC2 rs717620 might be potential clinical markers for predicting chemotherapy toxicity and response induced by platinum-based treatment in NSCLC patients.Trial registration Chinese Clinical Trial Registry ChiCTR-RNC-12002892

Pharmacogenomic Variants May Influence the Urinary Excretion of Novel Kidney Injury Biomarkers in Patients Receiving Cisplatin

“…The presence of the SLC22A2 variant was associated with maintenance of serum creatinine. The SLC22A2 polymorphism rs316019 (G808T; Ser270Ala) has also been associated with protection from cisplatin ototoxicity [ 36 ], odds of hepatotoxicity and hematologic toxicity secondary to platinum chemotherapy [ 37 ], and increased metformin renal and secretory clearance [ 38 ]. In the current study, patients heterozygous vs. homozygous wildtype for the SLC22A2 rs316019 polymorphism had associated higher concentrations and fold-changes in urinary KIM-1 at baseline, Day 3, and Day 10 as compared to wildtype homozygotes.…”

“…The transporters MATE1 and MRP2 are brush border proteins that efflux cisplatin from proximal tubule cells to urine and reduce the susceptibility to nephrotoxicity [ 18 , 19 ]. A previous publication noted that the SLC47A1 rs2289669 variant was linked to hematological toxicity secondary to platinum containing chemotherapy [ 37 ]. Using oxaliplatin as a substrate, an in vitro study with SLC47A1 -transfected variants in HEK-293 cells demonstrated loss of MATE1 function [ 42 ].…”

The association of genetic variations in DNA repair pathways with severe toxicities in NSCLC patients undergoing platinum‐based chemotherapy

“…As the genetic basis in platinum‐based therapy is much complicated, in addition to DNA repair pathway, the process of influx, detoxification and apoptosis may also exert influences on the effect of platinum agents . Single DNA biomarker may exhibit a slight effect on the clinical outcome .…”

ABCB1 c.3435C>T polymorphism is associated with platinum toxicity: a preliminary study

“…Other studies didn't find significant association between ABCB1 c.3435 C>T polymorphism and cisplatin toxicity [18,19,20]. Different genetic association results from different studies, may be explained by several factors such as the limited sample size of the patients included in the studies, heterogeneity of treatment protocols, treatment intent (curative vs palliative) and ethnicity.…”