Association Between NER And MMR Pathway Genetic Variations And Platinum-based Chemotherapeutic Efficacy

Background:Lung cancer is the most common cause of cancer deaths worldwide and platinum-based theropy have been considered to be the the main method for advanced-stage nonsmall-cell lung cancer(NSCLC).The difference in DNA repair capacity will lead to discrepancy in clinical effects of platinum-based therapy. Nucleotide excision repair pathway(NER) and mismatch repair(MMR) pathways are involved in the way platinum work.Aim:This article aimed at discussing the relationship between SNPs in nucleotide excision repair pathway(NER) and mismatch repair(MMR) pathways and response and toxicity of platinum-based therapy.Method:MassARRAY was used to detect31SNPs in NER and MMR pathway, and their effect on the chemosensitivity and toxicity were analyzed.Results:1) ERCC1Asn118Asn were associated with platinum resistance in NSCLC patients.T allele carriers presented with increased susceptibility to platinum resistance(OR=1.791, P=0.021). CSB Argl213Gly significantly correlated with better clinical benefit. Patients carrying rs2228527G allele tended to have a favorable prognosis after treatment with platinum-based chemotherapy(OR=0.434).2)In terms of grade3-4hematologic toxicity, XPC rs2228000(Ala499Va1)T carriers have a low risk of grade3-4hematologic toxicity(OR=0.523,P=0.005),Leukocytopenia(OR=0.442,P=0.013), Neutropenia (OR=0.522, P=0.016). XPF Ser835Ser C carriers have a high risk of grade3-4hematologic toxicity(OR=1.583, P=0.048), Thrombocytopenia(OR=3.402,P=0.006). In Recessive modle, RRM1C-37A C carriers have a high risk of3-4hematologic toxicity(OR=2.171, P=0.046), Leukocytopenia(OR=1.388,P=0.0004), ERCC1C8092A C carriers have a low risk of grade3-4hematologic toxicity(OR=0.300,P=0.014).3) In MMR pathway, CA+AA genotype of PMS2-22C>A have a decreased risk of grade3-4hematologic toxicity(OR=0.478,P=0.008), Leukocytopenia (OR=0.469,P=0.007),Neutropenia(OR=0.490,P=0.030). hMLHl-93G>A lowered the risk of grade3-4hematologic toxicity(OR=0.478, P=0.008), Leukocytopenia(OR=0.261, P=0.0002).Conclusion:Polymorphsms in NER,MMR pathway were significantly associated with platinum chemosensitivity and toxicity and may serve as the indicators of response and toxicity, and can further guide personalized medicine.