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Mir-pharmacogenetics of Vincristine and peripheral neurotoxicity in childhood B-cell acute lymphoblastic leukemia

The Pharmacogenomics Journal volume 18, pages 704–712 (2018)Cite this article

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Abstract

Vincristine (VCR), an important component of childhood acute lymphoblastic leukemia (ALL) therapy, can cause sensory and motor neurotoxicity. This neurotoxicity could lead to dose reduction or treatment discontinuation, which could in turn reduce survival. In this line, several studies associated peripheral neurotoxicity and polymorphisms in genes involved in pharmacokinetics (PK) and pharmacodynamics (PD) of VCR. Nowadays, it is well known that these genes are regulated by microRNAs (miRNAs) and SNPs in miRNAs could modify their levels or function. Therefore, the aim of this study was to determine whether SNPs in miRNAs could be associated with VCR-induced neurotoxicity. To achieve this aim, we analyzed all the SNPs in miRNAs (minor allele frequency (MAF) ≥ 0.01) which could regulate VCR-related genes in a large cohort of Spanish children with B-cell precursor ALL (B-ALL) homogeneously treated with LAL/SHOP protocols. We identified the A allele of rs12402181 in the seed region of miR-3117-3p, that could affect the binding with ABCC1 and RALBP1 gene, and C allele of rs7896283 in pre-mature sequence of miR-4481, which could be involved in peripheral nerve regeneration, significantly associated with VCR-induced neurotoxicity. These findings point out the possible involvement of two SNPs in miRNA associated with VCR-related neurotoxicity.

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Fig. 1
Fig. 2: Energy change (∆∆G) and minimum free-energy structures of the three most significant miRNA SNPs (a. miR-3117, b. miR-4481 and c. miR-6076) due to the presence of different alleles, extracted from RNAfold web tool. 

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References

  1. Johnston WT, Lightfoot TJ, Simpson J, Roman E. Childhood cancer survival: a report from the United Kingdom Childhood Cancer Study. Cancer Epidemiol 2010;34:659–66.

    Article  Google Scholar 

  2. Carozzi VA, Canta A, Chiorazzi A. Chemotherapy-induced peripheral neuropathy: What do we know about mechanisms? Neurosci Lett 2015;596:90–107.

    Article  CAS  Google Scholar 

  3. Gutierrez-Camino A, Martin-Guerrero I, Lopez-Lopez E, Echebarria-Barona A, Zabalza I, Ruiz I, et al Lack of association of the CEP72rs924607 TT genotype with vincristine-related peripheral neuropathy during the early phase of pediatric acute lymphoblastic leukemia treatment in a Spanish population. Pharm Genom 2016;26:100–2.

    Article  CAS  Google Scholar 

  4. Ceppi F, Langlois-Pelletier C, Gagne V, Rousseau J, Ciolino C, De Lorenzo S, et al Polymorphisms of the vincristine pathway and response to treatment in children with childhood acute lymphoblastic leukemia. Pharmacogenomics 2014;15:1105–16.

    Article  CAS  Google Scholar 

  5. Postma TJ, Benard BA, Huijgens PC, Ossenkoppele GJ, Heimans JJ. Long-term effects of vincristine on the peripheral nervous system. J Neurooncol 1993;15:23–27.

    Article  CAS  Google Scholar 

  6. Lopez-Lopez E, Gutierrez-Camino A, Astigarraga I, Navajas A, Echebarria-Barona A, Garcia-Miguel P, et al Vincristine pharmacokinetics pathway and neurotoxicity during early phases of treatment in pediatric acute lymphoblastic leukemia. Pharmacogenomics 2016;17:731–41.

    Article  CAS  Google Scholar 

  7. Diouf B, Crews KR, Lew G, Pei D, Cheng C, Bao J, et al Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia. JAMA 2015;313:815–23.

    Article  CAS  Google Scholar 

  8. Hartman A, van Schaik RHN, van der Heiden IP, Broekhuis MJC, Meier M, den Boer ML, et al Polymorphisms in genes involved in vincristine pharmacokinetics or pharmacodynamics are not related to impaired motor performance in children with leukemia. Leuk Res 2010;34:154–9.

    Article  CAS  Google Scholar 

  9. Moore AS, Norris R, Price G, Nguyen T, Ni M, George R, et al Vincristine pharmacodynamics and pharmacogenetics in children with cancer: a limited-sampling, population modelling approach. J Paediatr Child Health 2011;47:875–82.

    Article  Google Scholar 

  10. Egbelakin A, Ferguson MJ, MacGill EA, Lehmann AS, Topletz AR, Quinney SK, et al Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 2011;56: 361–7.

    Article  Google Scholar 

  11. Plasschaert SLA, Groninger E, Boezen M, Kema I, de Vries EGE, Uges D, et al Influence of functional polymorphisms of the MDR1 gene on vincristine pharmacokinetics in childhood acute lymphoblastic leukemia. Clin Pharmacol Ther 2004;76:220–9.

    Article  CAS  Google Scholar 

  12. Nakajima M, Yokoi T. MicroRNAs from biology to future pharmacotherapy: regulation of cytochrome P450s and nuclear receptors. Pharmacol Ther 2011;131:330–7.

    Article  CAS  Google Scholar 

  13. Li M-P, Hu Y-D, Hu X-L, Zhang Y-J, Yang Y-L, Jiang C, et al MiRNAs and miRNA polymorphisms modify drug response. Int J Environ Res Pub Health 2016;13:pii:E1096 https://doi.org/10.3390/ijerph13111096

    Article  CAS  Google Scholar 

  14. Gutierrez-Camino A, Oosterom N, den Hoed MAH, Lopez-Lopez E, Martin-Guerrero I, Pluijm SMF et al. The miR-1206 microRNA variant is associated with methotrexate-induced oral mucositis in pediatric acute lymphoblastic leukemia. Pharmacogenet Genome 2017;27:303–6.

    Article  CAS  Google Scholar 

  15. Lopez-Lopez E, Gutierrez-Camino A, Bilbao-Aldaiturriaga N, Pombar-Gomez M, Martin-Guerrero I, Garcia-Orad A. Pharmacogenetics of childhood acute lymphoblastic leukemia. Pharmacogenomics 2014;15:1383–98.

    Article  CAS  Google Scholar 

  16. Iparraguirre L, Gutierrez-Camino A, Umerez M, Martin-Guerrero I, Astigarraga I, Navajas A, et al MiR-pharmacogenetics of methotrexate in childhood B-cell acute lymphoblastic leukemia. Pharm Genom 2016;26:517–25.

    Article  CAS  Google Scholar 

  17. Sambrook JRD. Molecular cloning: a laboratory manual. 3rd edn. New York: NY: Cold Spring Harbor Laboratory Press; 2001.

    Google Scholar 

  18. Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I. Controlling the false discovery rate in behavior genetics research. Behav Brain Res 2001;125:279–84.

    Article  CAS  Google Scholar 

  19. Sullivan KM, Dean A, Soe MM. OpenEpi: a web-based epidemiologic and statistical calculator for public health. Public Health Rep 2009;124:471–4.

    Article  Google Scholar 

  20. Gruber AR, Lorenz R, Bernhart SH, Neubock R, Hofacker IL. The Vienna RNA websuite. Nucleic Acids Res 2008;36:W70–4.

    Article  CAS  Google Scholar 

  21. Dweep H, Sticht C, Pandey P, Gretz N. miRWalk--database: prediction of possible miRNA binding sites by ‘walking’ the genes of three genomes. J Biomed Inform 2011;44:839–47.

    Article  CAS  Google Scholar 

  22. Kamburov A, Stelzl U, Lehrach H, Herwig R. The ConsensusPathDB interaction database: 2013 update. Nucleic Acids Res 2013;41:D793–800.

    Article  CAS  Google Scholar 

  23. Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res 2017;45:D353–D361.

    Article  CAS  Google Scholar 

  24. Fabregat A, Sidiropoulos K, Garapati P, Gillespie M, Hausmann K, Haw R, et al The Reactome pathway Knowledgebase. Nucleic Acids Res 2016;44:D481–7.

    Article  CAS  Google Scholar 

  25. Kunicka T, Soucek P. Importance of ABCC1 for cancer therapy and prognosis. Drug Metab Rev 2014;46:325–42.

    Article  CAS  Google Scholar 

  26. Franca R, Rebora P, Bertorello N, Fagioli F, Conter V, Biondi A, et al Pharmacogenetics and induction/consolidation therapy toxicities in acute lymphoblastic leukemia patients treated with AIEOP-BFM ALL 2000 protocol. Pharm J 2017;17:4–10.

    CAS  Google Scholar 

  27. Awasthi S, Hallene KL, Fazio V, Singhal SS, Cucullo L, Awasthi YC, et al RLIP76, a non-ABC transporter, and drug resistance in epilepsy. BMC Neurosci 2005;6:61.

    Article  Google Scholar 

  28. Drake KJ, Singhal J, Yadav S, Nadkar A, Pungaliya C, Singhal SS, et al RALBP1/RLIP76 mediates multidrug resistance. Int J Oncol 2007;30:139–44.

    CAS  PubMed  Google Scholar 

  29. Gong J, Tong Y, Zhang H-M, Wang K, Hu T, Shan G, et al Genome-wide identification of SNPs in microRNA genes and the SNP effects on microRNA target binding and biogenesis. Hum Mutat 2012;33:254–63.

    Article  CAS  Google Scholar 

  30. Chiono V, Tonda-Turo C. Trends in the design of nerve guidance channels in peripheral nerve tissue engineering. Prog Neurobiol 2015;131:87–104.

    Article  Google Scholar 

  31. Lee YJD, Kim V, Muth DC, Witwer KW. Validated MicroRNA Target Databases: An Evaluation. Drug Dev Res 2015;76:389–96.

    Article  Google Scholar 

  32. Akhtar MM, Micolucci L, Islam MS, Olivieri F, Procopio AD. Bioinformatic tools for microRNA dissection. Nucleic Acids Res 2016;44:24–44.

    Article  CAS  Google Scholar 

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Acknowledgements

This project was supported by Basque Government (IT661-13 and IT989-16). Support by the Spanish National Genotyping Center (CeGen) is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, UPV/EHU, Leioa, Spain

    Ángela Gutierrez-Camino, Maitane Umerez, Idoia Martin-Guerrero, Borja Santos & Africa Garcia-Orad

  2. Department of Pediatrics, University Hospital Donostia, San Sebastian, Spain

    Nagore García de Andoin

  3. Department of Oncohematology, University Hospital La Paz, Madrid, Spain

    Ana Sastre

  4. Department of Pediatrics, University Hospital Cruces, Barakaldo, Spain

    Aizpea Echebarria-Barona & Itziar Astigarraga

  5. Department of Pediatrics, University of the Basque Country, UPV/EHU, Leioa, Spain

    Itziar Astigarraga & Aurora Navajas

  6. BioCruces Health Research Institute, Barakaldo, Spain

    Itziar Astigarraga, Aurora Navajas & Africa Garcia-Orad

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  1. Ángela Gutierrez-Camino
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  2. Maitane Umerez
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  3. Idoia Martin-Guerrero
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  9. Aurora Navajas
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  10. Africa Garcia-Orad
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Correspondence to Africa Garcia-Orad.

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The authors declare that they have no conflict of interest.

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Ángela Gutierrez-Camino, and Maitane Umerez, contibuted equally to this work.

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Gutierrez-Camino, Á., Umerez, M., Martin-Guerrero, I. et al. Mir-pharmacogenetics of Vincristine and peripheral neurotoxicity in childhood B-cell acute lymphoblastic leukemia. Pharmacogenomics J 18, 704–712 (2018). https://doi.org/10.1038/s41397-017-0003-3

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