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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.

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References

  1. Gagne JF, Montminy V, Belanger P, Journault K, Gaucher G, Guillemette C . Common human UGT1A polymorphisms and the altered metabolism of irinotecan active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). Mol Pharmacol 2002; 62: 608–617.

    Article  CAS  PubMed  Google Scholar 

  2. Barbarino JM, Haidar CE, Klein TE, Altman RB . PharmGKB summary: very important pharmacogene information for UGT1A1. Pharmacogenet Genomics 2014; 24: 177–183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. de Jong FA, Kitzen JJ, de Bruijn P, Verweij J, Loos WJ . Hepatic transport, metabolism and biliary excretion of irinotecan in a cancer patient with an external bile drain. Cancer Biol Ther 2006; 5: 1105–1110.

    Article  PubMed  Google Scholar 

  4. De Mattia E, Toffoli G, Polesel J, D'Andrea M, Corona G, Zagonel V et al. Pharmacogenetics of ABC and SLC transporters in metastatic colorectal cancer patients receiving first-line FOLFIRI treatment. Pharmacogenet Genomics 2013; 23: 549–557.

    Article  CAS  PubMed  Google Scholar 

  5. Marsh S, Hoskins JM . Irinotecan pharmacogenomics. Pharmacogenomics 2010; 11: 1003–1010.

    Article  CAS  PubMed  Google Scholar 

  6. Smith NF, Figg WD, Sparreboom A . Pharmacogenetics of irinotecan metabolism and transport: an update. Toxicol In Vitro 2006; 20: 163–175.

    Article  CAS  PubMed  Google Scholar 

  7. Innocenti F, Schilsky RL, Ramirez J, Janisch L, Undevia S, House LK et al. Dose-finding and pharmacokinetic study to optimize the dosing of irinotecan according to the UGT1A1 genotype of patients with cancer. J Clin Oncol 2014; 32: 2328–2334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Marcuello E, Paez D, Pare L, Salazar J, Sebio A, del Rio E et al. A genotype-directed phase I-IV dose-finding study of irinotecan in combination with fluorouracil/leucovorin as first-line treatment in advanced colorectal cancer. Br J Cancer 2011; 105: 53–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Toffoli G, Cecchin E, Gasparini G, D'Andrea M, Azzarello G, Basso U et al. Genotype-driven phase I study of irinotecan administered in combination with fluorouracil/leucovorin in patients with metastatic colorectal cancer. J Clin Oncol 2010; 28: 866–871.

    Article  CAS  PubMed  Google Scholar 

  10. Guillemette C, Levesque E, Rouleau M . Pharmacogenomics of human uridine diphospho-glucuronosyltransferases and clinical implications. Clin Pharmacol Ther 2014; 96: 324–339.

    Article  CAS  PubMed  Google Scholar 

  11. Cecchin E, Innocenti F, D'Andrea M, Corona G, De Mattia E, Biason P et al. Predictive role of the UGT1A1, UGT1A7, and UGT1A9 genetic variants and their haplotypes on the outcome of metastatic colorectal cancer patients treated with fluorouracil, leucovorin, and irinotecan. J Clin Oncol 2009; 27: 2457–2465.

    Article  CAS  PubMed  Google Scholar 

  12. Beutler E, Gelbart T, Demina A . Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci U S A 1998; 95: 8170–8174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hu ZY, Yu Q, Pei Q, Guo C . Dose-dependent association between UGT1A1*28 genotype and irinotecan-induced neutropenia: low doses also increase risk. Clin Cancer Res 2010; 16: 3832–3842.

    Article  CAS  PubMed  Google Scholar 

  14. Hu ZY, Yu Q, Zhao YS . Dose-dependent association between UGT1A1*28 polymorphism and irinotecan-induced diarrhoea: a meta-analysis. Eur J Cancer 2010; 46: 1856–1865.

    Article  CAS  PubMed  Google Scholar 

  15. Dias MM, McKinnon RA, Sorich MJ . Impact of the UGT1A1*28 allele on response to irinotecan: a systematic review and meta-analysis. Pharmacogenomics 2012; 13: 889–899.

    Article  CAS  PubMed  Google Scholar 

  16. Levesque E, Belanger AS, Harvey M, Couture F, Jonker D, Innocenti F et al. Refining the UGT1A haplotype associated with irinotecan-induced hematological toxicity in metastatic colorectal cancer patients treated with 5-fluorouracil/irinotecan-based regimens. J Pharmacol Exp Ther 2013; 345: 95–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Innocenti F, Liu W, Chen P, Desai AA, Das S, Ratain MJ . Haplotypes of variants in the UDP-glucuronosyltransferase1A9 and 1A1 genes. Pharmacogenet Genomics 2005; 15: 295–301.

    Article  CAS  PubMed  Google Scholar 

  18. Court MH, Freytsis M, Wang X, Peter I, Guillemette C, Hazarika S et al. The UDP-Glucuoronosyltransferase (UGT) 1A polymorphism c.2042C>G (rs8330) is associated with increased human liver acetaminophen glucuronidation, increased UGT1A Exon 5a/5b Splice Variant mRNA ratio, and decreased risk of unintentional acetaminophen-induced acute liver failure. J Pharmacol Exp Ther 2013; 345: 297–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Girard H, Thibaudeau J, Court MH, Fortier LC, Villeneuve L, Caron P et al. UGT1A1 polymorphisms are important determinants of dietary carcinogen detoxification in the liver. Hepatology 2005; 42: 448–457.

    Article  CAS  PubMed  Google Scholar 

  20. Girard H, Villeneuve L, Court MH, Fortier LC, Caron P, Hao Q et al. The novel UGT1A9 intronic I399 polymorphism appears as a predictor of 7-ethyl-10-hydroxycamptothecin glucuronidation levels in the liver. Drug Metab Dispos 2006; 34: 1220–1228.

    Article  CAS  PubMed  Google Scholar 

  21. Toffoli G, Cecchin E, Corona G, Russo A, Buonadonna A, D'Andrea M et al. The role of UGT1A1*28 polymorphism in the pharmacodynamics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer. J Clin Oncol 2006; 24: 3061–3068.

    Article  CAS  PubMed  Google Scholar 

  22. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Stephens M, Donnelly P . A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003; 73: 1162–1169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Stephens M, Smith NJ, Donnelly P . A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978–989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Johnson AD, Kavousi M, Smith AV, Chen MH, Dehghan A, Aspelund T et al. Genome-wide association meta-analysis for total serum bilirubin levels. Hum Mol Genet 2009; 18: 2700–2710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Angstadt AY, Hartman TJ, Lesko SM, Muscat JE, Zhu J, Gallagher CJ et al. The effect of UGT1A and UGT2B polymorphisms on colorectal cancer risk: haplotype associations and gene-environment interactions. Genes Chromosomes Cancer 2014; 53: 454–466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Fogarty MP, Panhuis TM, Vadlamudi S, Buchkovich ML, Mohlke KL . Allele-specific transcriptional activity at type 2 diabetes-associated single nucleotide polymorphisms in regions of pancreatic islet open chromatin at the JAZF1 locus. Diabetes 2013; 62: 1756–1762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sebio A, Paez D, Salazar J, Berenguer-Llergo A, Pare-Brunet L, Lasa A et al. Intergenic polymorphisms in the amphiregulin gene region as biomarkers in metastatic colorectal cancer patients treated with anti-EGFR plus irinotecan. Pharmacogenomics J 2014; 14: 256–262.

    Article  CAS  PubMed  Google Scholar 

  29. Stadhouders R, Aktuna S, Thongjuea S, Aghajanirefah A, Pourfarzad F, van Ijcken W et al. HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers. J Clin Invest 2014; 124: 1699–1710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Levesque E, Delage R, Benoit-Biancamano MO, Caron P, Bernard O, Couture F et al. The impact of UGT1A8, UGT1A9, and UGT2B7 genetic polymorphisms on the pharmacokinetic profile of mycophenolic acid after a single oral dose in healthy volunteers. Clin Pharmacol Ther 2007; 81: 392–400.

    Article  CAS  PubMed  Google Scholar 

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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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Correspondence to C Guillemette.

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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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