Genetic polymorphisms associated with oxaliplatin-induced peripheral neurotoxicity in Japanese patients with colorectal cancer

摘要

Objective: Pharmacogenomic associations between severe oxaliplatininduced chronic peripheral neurotoxicity (OXCPN) (Grade 2 lasting for > 7 days or Grade 3) and 9 single nucleotide polymorphisms (SNPs) in 8 genes (TAC1, FOXC1, ITGA1, ACYP2, DLEU7, BTG4, CAMK2N1, and FARS2) were reported by the genomewide association study (GWAS) in Korean patients. The present study was designed to explore reliable predictors of OXCPN and thereby improve the management of metastatic colorectal cancer (CRC). Methods: We retrospectively investigated pharmacogenomic characteristics of OXCPN in 70 Japanese patients with CRC who received oxali-platin- based chemotherapy and updated the results of our previous analysis of ERCC1 (C118T, rs11615 and C8092A, rs3212986) and GSTP1 (Ile105Val, rs1695) polymorphisms. Results: Univariate analysis suggested potential associations of severe OXCPN with rs843748 in ACYP2 and rs17140129 in FARS2, as well as with the absence of diabetes mellitus (DM) (p = 0.056, 0.072, and 0.029, respectively). There was no association between severe OXCPN and any of the 7 other SNPs. Multiple logistic regression analysis showed that an increased risk of severe OXCPN was related to rs17140129 and the absence of DM (p = 0.034 and 0.030, respectively). On updated analysis, polymorphisms of ERCC1 (C118T, rs11615) and rs10486003 in TAC1 were associated with time to the onset of Grade 1 OXCPN (p = 0.024 and 0.049, respectively). Conclusions: Severe OXCPN is significantly related to rs17140129, found in the GWAS of Korean patients, in Japanese patients. Patients without DM are more likely to have OXCPN. The association between ERCC1 polymorphism and time to the onset of OXCPN was significant on updated analysis.