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
Highlights
Platinum-based chemotherapy is the first-line treatment of non-small cell lung cancer (NSCLC); it is important to discover biomarkers that can be used to predict the efficacy and toxicity of this treatment
Seven single-nucleotide polymorphisms (SNPs) were genotyped in these patients, all of which were conformed in Hardy–Weinberg equilibrium (HWE) (P > 0.05)
These results indicate that G allele carriers of organic cation transporter 2 (OCT2) rs316019 polymorphisms have better tolerance to hematological toxicity and hepatotoxicity, whereas A allele carriers of rs2289669 polymorphisms have poor tolerance to hematological toxicity caused by platinum-based chemotherapy
Summary
Platinum-based chemotherapy is the first-line treatment of non-small cell lung cancer (NSCLC); it is 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. Organic cation transporter 2 (OCT2), encoded by the solute carrier family 22, member 2 (SLC22A2) gene, is a major transporter expressed on the basolateral domain of renal tubular cells in the kidney [9]. Multidrug and toxin extrusion 1 (MATE1), encoded by the solute carrier family 47, member 1 (SLC47A1) gene, was identified as an H+-coupled organic cation exporter [11] This transporter is mainly expressed on the luminal membranes of the renal urinary duct [12]. Studies have suggested that ABCC2 is involved in the excretion of organic anions, including cisplatin [17], and ABCC2 has been implicated in platinum resistance and associated toxicity [18]
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