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Impact of genetic polymorphisms determining leukocyte/neutrophil count on chemotherapy toxicity

The Pharmacogenomics Journal volume 18, pages 270–274 (2018)Cite this article

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Abstract

Neutropenia and infection are major dose-limiting side effects of chemotherapy. The risk of initial infection and subsequent complications are directly related to the depth and duration of neutropenia. Recent genome-wide association studies identified variants in DARC and CXCL2 genes, and in ORMDL3-GSDMA-CSF3 locus on chromosome 17q21 that influence white blood cell and neutrophil counts in healthy individuals. To investigate whether polymorphisms in these loci in conjunction with chemotherapy may modulate risk of treatment complications, we analyzed 21 SNPs across these genes for an association with chemotherapy-related neutropenia and infection in 286 Caucasian children with acute lymphoblastic leukemia. After correction for multiple testing, DARC polymorphism rs3027012 in 5′-UTR was associated with higher risk of low absolute phagocyte count (APC<500 and <1000 cells per microliter, P=0.001 and P<0.0005, respectively) and hospitalization due to febrile neutropenia (P=0.002). Protective effect was instead seen for DARC rs12075 A to G substitution (P=0.004). The SNP rs3859192 in the GSDMA were associated with hospitalization due to infection (P=0.004); infection was also modulated in the additive manner by the CXCL2 rs16850408 (P=0.002). This study shows for the first time that the variations in DARC, GSDMA and CXCL2 genes may play a role in the onset of chemotherapy complications.

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Acknowledgements

We thank all patients and their parents who consented to participate in genetics studies related to leukemia. Coast to Coast against Cancer Foundation, Leukemia Lymphoma Society of Canada, Canadian Institutes of Health Research and Charles Bruneau Foundation, supported this study.

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  1. Y D Pastore and M Krajinovic: Authors contributed equally to senior authorship.

Authors and Affiliations

  1. Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada

    S J Glisovic, Y D Pastore, V Gagne, M Plesa, C Laverdière, J M Leclerc, D Sinnett & M Krajinovic

  2. Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada

    S J Glisovic & M Krajinovic

  3. Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada

    Y D Pastore, C Laverdière, J M Leclerc, D Sinnett & M Krajinovic

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Correspondence to M Krajinovic.

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Glisovic, S., Pastore, Y., Gagne, V. et al. Impact of genetic polymorphisms determining leukocyte/neutrophil count on chemotherapy toxicity. Pharmacogenomics J 18, 270–274 (2018). https://doi.org/10.1038/tpj.2017.16

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