In this study, we investigated whether polymorphisms in transporter genes (OCT2, ABCB1, ABCC2, and MATE1) were associated with toxicity and the response to platinum-based chemotherapy in 403 NSCLC patients. We evaluated the associations of these gene polymorphisms with gastrointestinal toxicity, hematological toxicity, hepatotoxicity, and overall toxicity and performed a stratification analysis of overall toxicity to extract additional information. Our results showed that OCT2 rs316019 was associated with hepatotoxicity and hematological toxicity, whereas MATE1 rs2289669 was associated with hematological toxicity induced by platinum. However, there was no statistical association between either OCT2 rs316019 or MATE1 rs2289669 polymorphisms and the platinum-based chemotherapy response in these patients. We found that only ABCC2 rs717620 may be related to chemotherapy response in NSCLC patients.
Our results showed that OCT2 rs316019 was associated with platinum-induced hematological toxicity, hepatotoxicity, and overall toxicity. G allele carriers had better tolerance to hematological toxicity and hepatotoxicity after platinum-based chemotherapy. Moreover, NSCLC patients ?55 years old, non-smokers, or those diagnosed with squamous cell carcinoma carrying the G allele of OCT2 rs316019 presented a lower risk of overall severe toxicity than their counterparts. This polymorphism was also associated with chemotherapy toxicity for female patients in the present study. All these results indicated that OCT2 rs316019 was associated with reduced cisplatin-induced hematological toxicity and hepatotoxicity in Chinese NSCLC patients.
Numerous variations of the MATE1 gene have been determined to affect the clinical response to cationic drugs. It has also been reported that MATE1 transporter activity was reduced by rs2289669 [22]. Indeed, our results demonstrated that MATE1 rs2289669 was associated with hematological toxicity and overall toxicity during platinum-based chemotherapy. A allele carriers had poor tolerance to hematological toxicity and overall toxicity in the recessive model. Furthermore, NSCLC patients 55 years old in the recessive model, patients who were smokers in the additive and dominant models, and male patients in the additive and recessive models showed associations with overall toxicity in platinum-based chemotherapy.
ABCC2 is an efflux transporter expressed in the bile canalicular membrane, and this protein plays a primary role in the metabolism of many chemotherapeutic agents [23]. ABCC2 expression is present in many tumor tissues and may lead to multidrug resistance [18]. In 1999, it was found that ABCC2 modulated cisplatin resistance through glutathione transport; a mutation in ABCC2 could thus highly influence the sensitivity to cisplatin [24]. In the present study, ABCC2 rs717620 was demonstrated to be associated with the response to platinum-based chemotherapy. Patients who carried the A allele of the rs2289669 polymorphism had better tolerance to hematological toxicity. Furthermore, we found that the ABCC2 rs717620 polymorphism increased the sensitivity to platinum in patients diagnosed with adenocarcinoma, smoker patients, and male patients.
It should be noted that some previous studies reported results that are different from our present investigation. For example, one study showed no association between MATE1 rs2289669 and platinum toxicity. ABCC2 rs717620 had also been found to be moderately associated with a poor response to chemotherapy, which was opposite to our results [15]. Although the detailed reasons for these conflicting results remain unknown, we speculate that these inconsistencies maybe due to small sample sizes and different ethnic populations. In addition, when we calculated the P values for all the SNPs associated with toxicity and response with a false detection rate correction, no SNPs had a statistically significant association. Therefore, to obtain a more solid conclusion, independent replication studies with larger sample sizes should be performed in the future to validate our findings.