Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia

Response to glucocorticoid (GC) monotherapy in the initial phase of remission induction treatment in childhood acute lymphoblastic leukemia (ALL) represents important biomarker of prognosis and outcome. We aimed to study variants in several pharmacogenes (NR3C1, GSTs and ABCB1) that could contribute to improvement of GC response through personalization of GC therapy.

Methods

Retrospective study enrolling 122 ALL patients was carried out to analyze variants of NR3C1 (rs33389, rs33388 and rs6198), GSTT1 (null genotype), GSTM1 (null genotype), GSTP1 (rs1695 and rs1138272) and ABCB1 (rs1128503, rs2032582 and rs1045642) genes using PCR-based methodology. The marker of GC response was blast count per microliter of peripheral blood on treatment day 8. We carried out analysis in which cut-off value for GC response was 1000 (according to Berlin-Frankfurt-Munster [BFM] protocol), as well as 100 or 0 blasts per microliter.

Results

Carriers of rare NR3C1 rs6198 GG genotype were more likely to have blast count over 1000, than the non-carriers (p = 0.030). NR3C1 CAA (rs33389-rs33388-rs6198) haplotype was associated with blast number below 1000 (p = 0.030). GSTP1 GC haplotype carriers were more likely to have blast number below 1000 (p = 0.036), below 100 (p = 0.028) and to be blast negative (p = 0.054), while GSTP1 GT haplotype and rs1138272 T allele carriers were more likely to be blasts positive (p = 0.034 and p = 0.024, respectively). ABCB1 CGT (rs1128503-rs2032582-rs1045642) haplotype carriers were more likely to be blast positive (p = 0.018).

Conclusions

Our results have shown that NR3C1 rs6198 variant and GSTP1 rs1695-rs1138272 haplotype are the most promising pharmacogenomic markers of GC response in ALL patients.

Language:: English

Publication timeframe:: 4 times per year
Journal Subjects:: Medicine, Clinical Medicine, Internal Medicine, Haematology, Oncology, Radiology

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Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia

Vladimir Gasic

Branka Zukic

Biljana Stankovic

Dragana Janic

Lidija Dokmanovic

Jelena Lazic

Nada Krstovski

Vita Dolzan

Janez Jazbec

Sonja Pavlovic

Nikola Kotur

Article Category: Research Article

Published Online: Sep 11, 2018

Page range: 296 - 306

Received: Feb 19, 2018

Accepted: Apr 24, 2018

DOI: https://doi.org/10.2478/raon-2018-0034

Keywordspharmacogenomics, childhood ALL, glucocorticoids, glucocorticoid receptor gene, glutathione S-transferase genes, multidrug resistance 1 gene

© 2018 Vladimir Gasic, Branka Zukic, Biljana Stankovic, Dragana Janic, Lidija Dokmanovic, Jelena Lazic, Nada Krstovski, Vita Dolzan, Janez Jazbec, Sonja Pavlovic, Nikola Kotur, published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Background

Methods

Results

Conclusions

Keywords
pharmacogenomics, childhood ALL, glucocorticoids, glucocorticoid receptor gene, glutathione S-transferase genes, multidrug resistance 1 gene