IRINOTECANTOXICITY RELATED TO GILBERT´S SYNDROME   - COMPARISON OF THREE METHODS FOR GENOTYPING OF UGT1A1 (TA)_n

Abstract:

Gilbert’s syndrome (GS) occurs in approximately 10% of the European population. The most common cause is homozygosity for UGT1A1'28, which is a TA repeat expansion in the promoter of UGT1A1. It is characterised by intermittent hyperbilirubinemia due to reduced hepatic activity of the  enzyme UDP-glucuronosyl-transferase 1A1(UGT1A1). GS also  alteres the pharmacokinetics of some drugs and increases the risk of drug toxicity. Irinotecan (Camptosar®, Campto®) is used in metastatic colorectal cancer and the active metabolite is inactivated by UGT1A1. Studies have shown that GS can be a risk factor for toxicity during irinotecan therapy.

Three different methods for genotyping of UGT1A1'28 have been tested.

PCR with electrophoresis used for size separation, melting temperature analysis and fluorescent PCR followed by fragment analysis on a capillary sequencer.

The last method was found to be superior. This method was used for genotyping of patients with colorectal cancer treated with irinotecan and 5-fluorouracil in the Nordic VI study. A significant association between UGT1A1 genotype and plasma bilirubin level before the start of irinotecan treatment was seen (ANOVA p<0.0001). Patients with GS had an overall increased risk of adverse drug reactions (Fishers Exact test p=0.02).

Gilbert’s syndrome can be diagnosed by genotyping UGT1A1'28 with a fragment analysis method. Genotyping of UGT1A1'28 can be used to identify patients with an increased risk of adverse reactions to irinotecan.