UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil

Figure 1 Schematic diagram of UDP-glucuronosyltransferase1A1 and thymidylate synthetase. A: UDP-glucuronosyltransferase1A1 (UGT1A1) is the main enzyme involved in the glucuronidation of SN-38 (SN-38G). Single-nucleotide polymorphisms (SNPs) of UGT1A1 are the key factor in irinotecan metabolism; B: Thymidylate synthetase (TS) is the main target of 5-fluorouracil (5-FU). The ternary complex of TS, active metabolite of 5-FU (FdUMP) and methyl-tetra-hydrofolic acid (MTHF) inhibits DNA synthesis. SNP of TS affects the expression of enzyme and 5-FU efficacy. CES: Carboxylesterases; TOP1: Topoisomerase-1.

Figure 2 Analysis of UDP-glucuronosyltransferase1A1*28 and *6 by DNA sequencing and thymidylate synthetase by restriction fragment length polymorphism. A: 211G>A of UDP-glucuronosyltransferase1A1 (UGT1A1)*6; B: (TA) nTAA variant of UGT1A1*28; C: Polymerase chain reaction-based restriction fragment length polymorphism for 2R or 3R and G>C single-nucleotide polymorphism in 3R located in the 5’-UTR region of the thymidylate synthetase gene.

Figure 3 Time to progression and overall survival according to UDP-glucuronosyltransferase1A1*28 genotypes. A: Time to progression (TTP): Patients with TA6/6 were 5.97 (95%CI: 3.85-8.09), patients with TA6/7 and TA7/7 were 4.00 (95%CI: 1.15-6.85), P = 0.154; B: Overall survival (OS): Patients with TA6/6 were 18.00 (95%CI: 10.77-25.23), patients with TA6/7 and TA7/7 were 14.90 (95%CI: 7.58-22.22), P = 0.444. No significant difference was found between TA6/6 (wild type) and mutated genotypes. UGT1A1: UDP-glucuronosyltransferase1A1.

Figure 4 Area under concentration curve ratios of SN-38G/SN-38 comparison according to UDP-glucuronosyltransferase1A1*28 genotypes and UDP-glucuronosyltransferase1A1*28 + *6 group. A: Area under concentration curve (AUC) ratios comparison by UDP-glucuronosyltransferase1A1 (UGT1A1)*28: The AUC ratio of TA7/7 was less than half of the TA6/6 ratio (1.488 vs 3.178, P = 0.158); B: AUC ratios comparison by UGT1A1*28 + *6 group: Lower AUC ratio was found in the double mutation group (TA6/7 + G/A and TA7/7 + G/G), compared with the other two groups [wild type or single mutation group (1.488 vs 3.177, P = 0.078)].