Refining the UGT1A haplotype associated with irinotecan-induced hematological toxicity in metastatic colorectal cancer patients treated with 5-fluorouracil/irinotecan-based regimens

Éric Lévesque, Anne Sophie Bélanger, Mario Harvey, Félix Couture, Derek Jonker, Federico Innocenti, Erica Cecchin, Giuseppe Toffoli, Chantal Guillemette

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Abstract

Despite the importance of UDP-glucuronosyltransferase (UGT) 1A1*28 in irinotecan pharmacogenetics, our capability to predict drug-induced severe toxicity remains limited. We aimed at identifying novel genetic markers that would improve prediction of irinotecan toxicity and response in advanced colorectal cancer patients treated with folic acid (leucovorin), fluorouracil (5-FU), and irinotecan (camptosar)-based regimens. The relationships between UGT1A candidate markers across the gene (n = 21) and toxicity were prospectively evaluated in 167 patients. We included variants in the 3′untranscribed region (3′UTR) of the UGT1A locus, not studied in this context yet. These genetic markers were further investigated in 250 Italian FOLFIRI-treated patients. Several functional UGT1A variants, including UGT1A1*28, significantly influenced risk of severe hematologic toxicity. As previously reported in the Italian cohort, a 5-marker risk haplotype [haplotype II (HII); UGTs 1A9/1A7/1A1] was associated with severe neutropenia in our cohort [odds ratio (OR) = 2.43; P = 0.004]. The inclusion of a 3′UTR singlenucleotide polymorphism (SNP) permitted refinement of the previously defined HI, in which HIa was associated with the absence of severe neutropenia in combined cohorts (OR = 0.55; P = 0.038). Among all tested UGT1A variations and upon multivariate analyses, no UGT1A1 SNPs remained significant, whereas three SNPs located in the central region of UGT1A were linked to neutropenia grade 3-4. Haplotype analyses of these markers with the 3′UTR SNP allowed the identification of a protective HI (OR = 0.50; P = 0.048) and two risk haplotypes, HII and HIII, characterized by 2 and 3 unfavorable alleles, respectively, revealing a dosage effect (ORs of 2.15 and 5.28; P ≤ 0.030). Our results suggest that specific SNPs in UGT1A, other than UGT1A1*28, may influence irinotecan toxicity and should be considered to refine pharmacogenetic testing.

Original languageEnglish
Pages (from-to)95-101
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume345
Issue number1
DOIs
Publication statusPublished - Apr 2013

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irinotecan
Fluorouracil
Haplotypes
Colorectal Neoplasms
Neutropenia
Single Nucleotide Polymorphism
Odds Ratio
Genetic Markers
Leucovorin
Pharmacogenetics
Folic Acid
Multivariate Analysis
Alleles

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

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Refining the UGT1A haplotype associated with irinotecan-induced hematological toxicity in metastatic colorectal cancer patients treated with 5-fluorouracil/irinotecan-based regimens. / Lévesque, Éric; Bélanger, Anne Sophie; Harvey, Mario; Couture, Félix; Jonker, Derek; Innocenti, Federico; Cecchin, Erica; Toffoli, Giuseppe; Guillemette, Chantal.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 345, No. 1, 04.2013, p. 95-101.

Research output: Contribution to journalArticle

Lévesque, Éric ; Bélanger, Anne Sophie ; Harvey, Mario ; Couture, Félix ; Jonker, Derek ; Innocenti, Federico ; Cecchin, Erica ; Toffoli, Giuseppe ; Guillemette, Chantal. / Refining the UGT1A haplotype associated with irinotecan-induced hematological toxicity in metastatic colorectal cancer patients treated with 5-fluorouracil/irinotecan-based regimens. In: Journal of Pharmacology and Experimental Therapeutics. 2013 ; Vol. 345, No. 1. pp. 95-101.
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AU - Couture, Félix

AU - Jonker, Derek

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