The Association Between Single Nucleotide Polymorphism In The COX-2/PGES/EP Signaling Pathway And The Capecitabine Metabolism Pathway And Risk Of Hand Foot Syndrome In Patients Taking Capecitabine

Purpose:Capecitabine is a5-fluorouracil oral prodrug widely used in the clinic. Hand foot syndrome(HFS) is the most common adverse event of it. The pathogenesis of HFS remains unclear, most clinicians consider it as a type of inflammation conducted by cyclooxygenase-2(COX-2). Clinical trials also revealed that COX-2inhibitor celecoxib can significantly reduce the incidence of HFS in patients taking capecitabine. The COX-2/PGES/EP signaling pathway plays an important role in inflammatory reaction, We hypothesized that the single nucleotide polymorphism in this pathway may be associated with the risk of HFS induced by capecitabine.Methods:Using DNA from blood samples of225patients taking capecitabine, we tested19SNPs in six core genes (COX-2, PGES, EP1, EP2and EP4). Common Terminology Criteria for Adverse Events version3.0was used to grade Hand foot syndrome. We used Logistic regression analysis to evaluate the effect of various patient and clinical characteristics on the risk of grade≥2HFS. The cumulative incidence of grade≥2HFS was assessed by Kaplan-Meier analysis.Results:Among the225participants, there were129men and96women, including colorectal cancer (56.4%) and gastric cancer(43.6%). Most (58.6%) of the patients developed into HFS, including93grade1HFS,23grade2HFS and16grade3HFS. In Logistic regression analysis, we found that age≥54years and high dose(625-1000mg/m2) were risk factors, but did not reach the significant level (P was0.065,0.058respectively). Multivariate logistic regression analysis showed the AG/GG genotype of rs3810255to be associated with a significantly higher risk of grade≥2HFS, while the AG/AA genotype of rs17131450to be associated with a significantly lower risk of grade≥2HFS (OR=3.646, P=0.012; and OR=0.266,p=0.037; respectively), after adjustment for sex, patient age, disease stage, Karnofsky Performance Status, and dose.Conclusion:Our study showed that rs3810255GA/GG genotypes and rs17131450GA/GG genotypes to be associated with HFS in patients taking capecitabine. After validation, this finding may serve as a new predictor of HFS. Purpose:The activity of enzymes in the capecitabine metabolism pathway has been suggested to be a mechanism of hand foot syndrome (HFS) induced by capecitabine. several foreign studies had explored the association between single nucleotide polymorphism in the capecitabine metabolism pathway and risk of HFS, nevertheless, the results of different studies were inconsistent and there was no such study in the Chinese Han Population. We aimed to investigate this association in the Chinese Han Population.Methods:The genomic DNA was extracted from blood samples of225patients taking capecitabine. We tested13SNPs in five core genes (TP, CDD, DPD, TS and MTHFR) by MALDI-TOF (matrix-assisted laser desorption/ionization-time of flight). Logistic regression analysis was used to evaluate the effect of various patient and clinical characteristics on the risk of grade≥2HFS. And Kaplan-Meier analysis was used to assess the cumulative incidence of grade≥2HFS.Results:After adjustment of sex, age, disease stage, Karnofsky Performance Status, and dose of capecitabine, the Multivariate logistic regression analysis showed two SNPs (rs2853533and rs2847153) of TS were associated with risk of HFS. For rs2853533, The incidence of grade>2HFS in patients with CG/GG genotype was higher than that of CC genotype(OR=2.752, P=0.028). As for rs2847153, The incidence of grade≥2HFS in patients with AG/AA genotype was lower than that of GG genotype(OR=0.460, P=0.035).Conclusion:Our study revealed two new SNPs (rs2853533and rs2847153) in capecitabine metabolism pathway to be associated with HFS, but also need conformation in a large population.