Glutathione S-transferase gene polymorphic sequence variations: Association with risk and response to Imatinib among Chronic Myeloid Leukemia patients of Kashmir

Shahid M Baba; Zafar A Shah; Arshad A Pandith; Sajad A Geelani; Mohammad M Mir; Javid R Bhat; Ayaz Gul; Gul M Bhat

doi:10.1111/ijlh.13471

Glutathione S-transferase gene polymorphic sequence variations: Association with risk and response to Imatinib among Chronic Myeloid Leukemia patients of Kashmir

Int J Lab Hematol. 2021 Oct;43(5):1000-1008. doi: 10.1111/ijlh.13471. Epub 2021 Jan 20.

Authors

Shahid M Baba¹, Zafar A Shah¹, Arshad A Pandith², Sajad A Geelani³, Mohammad M Mir⁴, Javid R Bhat³, Ayaz Gul¹, Gul M Bhat⁵

Affiliations

¹ Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India.
² Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India.
³ Department of Clinical Hematology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India.
⁴ Department of Basic Medical Sciences, University of Bisha, Bisha, Kingdom of Saudi Arabia.
⁵ Department of Medical Oncology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India.

PMID: 33470551
DOI: 10.1111/ijlh.13471

Abstract

Introduction: Glutathione S-transferase (GST) gene deletion or polymorphic sequence variations lead to decreased enzyme activity that influences susceptibility and response to tyrosine kinase inhibitors in chronic myeloid leukemia (CML). We aimed to analyze relation of different GST gene sequence variants with susceptibility and response to Imatinib in CML.

Material and methods: A total of 150 CML cases and equal number of age and gender matched healthy controls were genotyped for five GST polymorphisms by multiplex-PCR and PCR-RFLP techniques. BCR-ABL1 transcripts were quantified by quantitative Real Time PCR (qRT-PCR).

Results: GSTT1, GSTO1, and GSTO2 SNPs revealed no association, while as GSTM1_null genotype was observed to protect against the development of CML (OR = 0.53, P = .01). GSTP1 variant genotypes AG (OR = 2.1, P = .003) and GG (OR = 5.6, P < .001), significantly associated with increased risk of CML. Combined genotype analysis showed protective impact of GSTT1_present /GSTM1_null (OR = 0.44, P = .003) while as GSTT1_present /GSTP1-GG (OR = 6.92, P < .001) and GSTM1_present /GSTP1-GG (OR = 6.33, P < .001), significantly increased CML risk. GSTM1_null genotype individually and in combination with GSTT1_present associated with superior rate of major molecular response (MMR) and event free survival (EFS) (log-rank P = .029). GSTO2-AG+GG genotype associated with significantly inferior MMR rates at 3, 6, and 12 months. Also, patients with GSTO2-GG genotype showed significantly reduced EFS (log-rank P = .025). Multivariate analysis confirmed GSTM1_null as a better (HR:0.19, P = .029) and GSTO2-GG genotype as an independent poor prognostic factor (HR:2.29, P = .037).

Conclusion: GSTM1_null genotype seems to have a better prognostic role while GSTP1 variants significantly increase CML risk. Also, results support a correlation between disease outcome and GSTO2 polymorphism.

Keywords: BCR-ABL1; GST02; GSTO1; Kashmir; chronic myeloid leukemia; event free survival; major molecular response; tyrosine kinase inhibitors.

MeSH terms

Adult
Antineoplastic Agents / therapeutic use*
Female
Gene Deletion
Glutathione Transferase / genetics*
Humans
Imatinib Mesylate / therapeutic use*
India / epidemiology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / epidemiology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
Male
Polymorphism, Single Nucleotide / drug effects
Risk Assessment
Treatment Outcome

Substances

Antineoplastic Agents
Imatinib Mesylate
glutathione S-transferase T1
GSTO1 protein, human
GSTO2 protein, human
Glutathione Transferase