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.
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Acknowledgements
We thank all participants in this study and the research nurses from Québec and Ottawa hospitals for their contributions. The Canadian Institutes of Health Research (CG; grant MOP-42392) and the Canada Research Chair Program (CG) supported this work. SC was a recipient of the studentship award ‘Fonds de l’Enseignement et de la Recherche’ from Faculty of Pharmacy at Laval University. IL is a recipient of a Canadian Institutes of Health Research Frederick Banting and Charles Best studentship award and a Graduate Scholarship for clinician-scientist from FRQ-S. MHC was supported by the United States National Institutes of Health, National Institute of General Medical Sciences (Grant GM-102130) and the William R. Jones Endowment at Washington State University. EL is a recipient of a Canadian Institutes of Health Research clinician-scientist phase II award and Prostate Cancer Canada Rising Star Award (RS2013-55). CG holds a Canada Research Chair in Pharmacogenomics (Tier I).
Author Contributions
Designed Research and supervision: Chantal Guillemette.
Patients’ recruitment, clinical data and provision of human livers: Derek Jonker, Félix Couture, Erica Cecchin, Giuseppe Toffoli, Eric Lévesque and Michael H. Court.
Performed Research: Sylvia Chen, Isabelle Laverdiere, Lyne Villeneuve and Mario Harvey.
Analyzed Data: Sylvia Chen, Isabelle Laverdiere, Alan Tourancheau, Lyne Villeneuve, Mario Harvey, Eric Lévesque and Chantal Guillemette.
Wrote Manuscript: Sylvia Chen, Isabelle Laverdiere, Eric Lévesque and Chantal Guillemette.
Critical revision of the manuscript for important intellectual content: All authors.
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Chen, S., Laverdiere, I., Tourancheau, A. et al. A novel UGT1 marker associated with better tolerance against irinotecan-induced severe neutropenia in metastatic colorectal cancer patients. Pharmacogenomics J 15, 513–520 (2015). https://doi.org/10.1038/tpj.2015.12
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DOI: https://doi.org/10.1038/tpj.2015.12
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