Relevance of Different UGT1A1 Polymorphisms in Irinotecan-Induced Toxicity

Abstract

Purpose: We wanted to assess polymorphisms in the uridine diphosphoglucuronosyl transferase 1A1 (UGT 1A1) gene: the TATA box polymorphism and UGT 1A1 G71R and Y486D mutations in the coding sequence, the main mutations characterizing Gilbert's syndrome, as predictors of severe toxic event occurrence after irinotecan (CPT-11) administration. Therefore, we set up a rapid, sensitive, and reliable technique in routine practice to detect before CPT-11 treatment, the at-risk patients.Experimental Design: Seventy-five patients with advanced colorectal cancer and treated with CPT-11 and 5-fluorouracil, entered the study. We used the Pyrosequencing technology a real-time sequencing method, to detect the UGT 1A1 TATA box polymorphisms and mutations in the coding regions. Patients were also assessed for both biochemical and clinical evaluation and tolerance to treatment.Results: No G71R and Y486D mutations were found in our population. Frequencies for UGT 1A1 TATA box polymorphisms were 41, 47, and 9% for wild-type 6/6, heterozygous 6/7, and Gilbert's syndrome 7/7, respectively. Tolerance to treatment decreased with increased number of TA repeat with 71% of the patients in 7/7 group who experienced grade 3/4 toxicity.Conclusions: The method we set up is suitable for the detection of UGT 1A1 polymorphism in routine practice before irinotecan treatment. It could help to detect the patients homozygous or heterozygous for Gilbert's syndrome, at-risk of CPT 11-induced toxicity, and thus could help to individualize the dose to optimize efficacy and limit toxicity.

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

“…It was concluded that the UGT1A1*28 genotype correlates with severe neutropenia upon irinotecan treatment. Rouits et al (2004) obtained results similar to Innocenti et al with respect to neutropenia in 75 advanced CRC patients receiving CPT-11 þ 5-fluorouracil. Five of seven homozygous 7/7 patients had severe neutropenia, compared with 14 of 35 6/7 patients and only three of 31 6/6 patients.…”

Association study between single-nucleotide polymorphisms in 199 drug-related genes and commonly measured quantitative traits of 752 healthy Japanese subjects

“…20,21 The clinical application of the genetic test for the UGT1A1*28 allele before irinotecan therapy has been in practice in the United States since 2005, based on a cumulative evidence supporting the significant association of this variant with severe irinotecan toxicity. 20,[22][23][24][25] The five most associated SNPs included rs4148323 (G4A, UGT1A1*6). Homozygotes of the UGT1A1*6 allele showed significantly high values in serum total bilirubin levels, supporting the evidence from earlier studies.…”

UGT1A1 promoter polymorphism increases risk of nilotinib-induced hyperbilirubinemia

“…The number of such cases was too small to allow them to be treated as independent genotype classes, and the details of their expected effects are not clear enough 16 to warrant grouping them with other genotypes. In addition to (A(TA)nTAA), other UGT1A1 polymorphisms 17,18 and haplotypes 19 have been associated with bilirubin levels and Gilbert's syndrome. These may prove to be more effective biomarkers of hyperbilirubinemia risk than the promoter polymorphism alone.…”