Lung cancer is the greatest contributor to tumor-derived death. Traditionally, platinum-based chemotherapies are the primary treatment for most patients. However, intrinsic drug resistance and side effects limit the efficacy of platinum-based chemotherapies. Previous studies demonstrated that Pol ζ can modulate cellular sensitivity to chemotherapy. The primary aim of this study was to investigate the potential role of the polymorphism of Pol ζ in platinum-based chemotherapy tolerance and side effects. A total of 663 patients who were newly histologically diagnosed with advanced NSCLC were enrolled. Their treatment response was classified into four categories: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). The gastrointestinal and hematological toxicity incidence was assessed twice a week during the entire first line of treatment. Thirteen SNPs of REV3 and REV7 were genotyped. The associations between SNPs and the treatment response or toxicity were analyzed with a logistic regression model. We discovered that five SNPs were correlated with the treatment response. Specifically, rs240969 was significantly associated with the treatment response, after a Bonferroni correction, in smokers and a combined cohort (P=0.048 and P=0.0082, respectively) as well as with rs3218573 in smokers (P=0.036). In addition, we discovered that the incidence of grade 3 or 4 gastrointestinal toxicity was significantly higher in patients carrying a G/G genotype of rs240966 or an A allele of rs456865. We also identified that five SNPs, namely rs240966, rs4945880, rs465646, rs2233025 and rs2336030, that were correlated with an increased risk of grade 3 or grade 4 hematologic toxicity. The REV3 and REV7 polymorphisms are in a catalytic subunit and an accessory subunit of Pol ζ, respectively, and participate in platinum-chemotherapy tolerance and side effects.
Keywords: Pol ζ; REV3; REV7; platinum-based chemotherapies; toxicity.; translesion synthesis.