Polymorphic markers associated with severe oxaliplatin‐induced, chronic peripheral neuropathy in colon cancer patients

Abstract

To identify potential genetic markers for severe oxaliplatin-induced chronic peripheral neuropathy (OXCPN), the authors performed a genome-wide association analysis of patients with colon cancer who received oxaliplatin-based chemotherapy. This was a prospective study in which DNA was purified in peripheral blood from patients with colon cancer who received oxaliplatin. The primary endpoint was the development of severe (grade 2 lasting for >7 days or grade 3) OXCPN. For the discovery set, genotyping was done for 96 patients who received adjuvant fluorouracil and oxaliplatin using the a genome-wide human single-nucleotide polymorphism (SNP) array. An association between polymorphisms and severe OXCPN was investigated. At the same time, 247 patients who received oxaliplatin-based, first-line chemotherapy for advanced disease were enrolled as a validation set. Among the 32 genotyped candidate SNPs selected from the discovery set, 9 SNPs in 8 genes (tachykinin, precursor 1[TAC1]; forkhead box C1 [FOXC1]; integrin, alpha 1 [ITGA1]; acylphosphatase 2, muscle type [ACYP2]; deleted in lymphocytic leukemia, 7 [DLEU7]; B-cell translocation gene 4 [BTG4]; calcium/calmodulin-dependent protein kinase II inhibitor 1 [CAMK2N1]; and phenylalanyl-tRNA synthase 2 [FARS2]) had nominal replication (P < .05). The most significant association was observed at reference SNP number (rs)10486003 in TAC1 (P = 4.84 × 10(-7)) in combined data from 2 sets. Five SNPs (rs10486003, rs2338, rs830884, rs843748, and rs797519) were significant in a multiple regression analysis (P < .05). Overall prediction accuracy calculated by the regression model was 72.8% (95% confidence interval, 65.8%-79.9%) in the model development and 75.9% (95% confidence interval, 66.9%-84.9%) in the model evaluation. The current results indicated that a genome-wide pharmacogenomic approach is useful for identifying novel polymorphism predictors of severe OXCPN that may be used in personalized chemotherapy.