title: A novel UGT1 marker associated with better tolerance against irinotecan-induced severe neutropenia in metastatic colorectal cancer patients.
abstract: The risk of severe irinotecan-induced neutropenia has been shown to be related to the UGT1 variant UGT1A1*28, which increases exposure to the potent metabolite SN-38. Our goal was to identify a novel UGT1 marker(s) using 28 haplotype-tagged single nucleotide polymorphisms genotyped by mass spectrometry. By characterizing the UGT1 sequence from a cohort of 167 Canadian metastatic colorectal cancer (mCRC) patients and a validation cohort of 250 Italian mCRC patients, we found rs11563250G, located in the intergenic region downstream of UGT1, to be significantly associated with reduced risk of severe neutropenia (odds ratio (OR)=0.21; P=0.043 and OR=0.27; P=0.036, respectively, and OR=0.31 when combined; P=0.001), which remained significant upon correction for multiple testing in the combined cohort (P=0.041). For the two-marker haplotype rs11563250G and UGT1A1*1 (rs8175347 TA6), the OR was of 0.17 (P=0.0004). Genetic testing of this marker may identify patients who might benefit from increased irinotecan dosing.
authors.affiliation: Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Québec, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.affiliation: Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Québec, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Laverdiere
authors.affiliation: Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Québec, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Tourancheau
authors.affiliation: Division of Medical Oncology, Department of Medicine, Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Jonker
authors.affiliation: Centre Hospitalier Universitaire de Québec Research Center and Faculty of Medicine, Laval University, Québec, Québec, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Couture
authors.affiliation: Division of Experimental and Clinical Pharmacology, Department of Molecular Biology and Translational Research, National Cancer Institute and Cancer for Molecular Biomedicine, Aviano, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Cecchin
authors.affiliation: Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Québec, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Villeneuve
authors.affiliation: Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Québec, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Harvey
authors.affiliation: Individualized Medicine Program, Department of Veterinary Clinical Sciences, Washington State University College of Veterinary Medicine, Pullman, WA, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Court
authors.affiliation: Division of Pharmacotherapy & Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: F
authors.initials: F
authors.lastname: Innocenti
authors.affiliation: Division of Experimental and Clinical Pharmacology, Department of Molecular Biology and Translational Research, National Cancer Institute and Cancer for Molecular Biomedicine, Aviano, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Toffoli
authors.affiliation: Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Québec, Canada.|Centre Hospitalier Universitaire de Québec Research Center and Faculty of Medicine, Laval University, Québec, Québec, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Lévesque
authors.affiliation: Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Québec, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Guillemette
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002170:Canada; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005820:Genetic Testing / Q000379:methods; D014453:Glucuronosyltransferase / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme