title: Refining the UGT1A haplotype associated with irinotecan-induced hematological toxicity in metastatic colorectal cancer patients treated with 5-fluorouracil/irinotecan-based regimens.
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 single-nucleotide 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.
authors: Pharmacogenomics Laboratory, Centre Hospitalier de l’Université Laval (CHU de Québec) Research Center and Faculty of Pharmacy, Laval University, Quebec, Canada.
authors: Eric
authors: E
authors: Lévesque
authors: Anne-Sophie
authors: AS
authors: Bélanger
authors: Mario
authors: M
authors: Harvey
authors: Félix
authors: F
authors: Couture
authors: Derek
authors: D
authors: Jonker
authors: Federico
authors: F
authors: Innocenti
authors: Erica
authors: E
authors: Cecchin
authors: Giuseppe
authors: G
authors: Toffoli
authors: Chantal
authors: C
authors: Guillemette
mesh_terms: D020413:3' Untranslated Regions; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use / Q000633:toxicity; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D005819:Genetic Markers; D014453:Glucuronosyltransferase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009503:Neutropenia / Q000139:chemically induced* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012720:Severity of Illness Index; D000099148:UGT1A1 Enzyme
chemical_list: D020413:3' Untranslated Regions; D002166:Camptothecin; D005472:Fluorouracil; D005819:Genetic Markers; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D002955:Leucovorin; D000099148:UGT1A1 Enzyme
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