GSTT1 null and rs156697 Polymorphism in GSTO2 Influence the Risk and Therapeutic Outcome of B-Acute Lymphoblastic Leukemia Patients

Shahid M Baba; Arshad A Pandith; Zafar A Shah; Sajad A Geelani; Javid R Bhat; Ayaz Gul; Sameer A Guru; Hamed A El-Serehy; Abid M Koul; Sheikh Mansoor

doi:10.3389/fonc.2021.714421

GSTT1 _null and rs156697 Polymorphism in GSTO2 Influence the Risk and Therapeutic Outcome of B-Acute Lymphoblastic Leukemia Patients

Front Oncol. 2021 Oct 14:11:714421. doi: 10.3389/fonc.2021.714421. eCollection 2021.

Authors

Affiliations

¹ Department of Immunology and Molecular Medicine, Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, India.
² Advanced Centre for Human Genetics, SKIMS, Srinagar, India.
³ Department of Clinical Hematology, SKIMS, Srinagar, India.
⁴ Department of Developmental and System Biology, Lurie Children's Hospital Northwest University, Chicago, IL, United States.
⁵ Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia.

Abstract

Introduction: Glutathione S-transferase (GST) gene deletion or polymorphic sequence variations lead to decreased enzyme activity that influences susceptibility and response to chemotherapy in acute lymphoblastic leukemia (ALL). This case-control study investigated the association of GST gene polymorphisms with the etiology and therapeutic outcome of B-ALL among Kashmiri population.

Methods: A total of 300 individuals including 150 newly diagnosed B-ALL patients and an equal number of age and gender matched controls were genotyped for five GST gene polymorphisms by polymerase chain reaction-restriction fragment length polymorphism technique (PCR-RFLP) and multiplex PCR techniques.

Results: Higher frequency of GSTT1 _null, GSTO2-AG, and GSTO2-GG genotypes was observed in ALL cases compared to controls that associated significantly with ALL risk (GSTT1 _null: OR = 2.93, p = 0.0001; GSTO2-AG: OR = 2.58, p = 0.01; GSTO2-GG: OR = 3.13, p = 0.01). GSTM1, GSTP1, and GSTO1 SNPs showed no significant association (p > 0.05). Combined genotype analysis revealed significant association of GSTT1 _null/GSTM1 _null (OR = 4.11, p = 0.011) and GSTT1 _null/GSTP1-AG (OR = 4.93, p = 0.0003) with B-ALL susceptibility. Haplotype analysis of rs4925 and rs156697 revealed that carriers of CG haplotype had increased risk of B-ALL (p = 0.04). Kaplan-Meier plots revealed significantly inferior 3-year disease-free survival for GSTO2-GG carriers (p = 0.002). Multivariate analysis confirmed GSTO2-GG as an independent poor prognostic factor for DFS (HR = 4.5, p = 0.034). Among combined genotypes, only GSTT1 _null/GSTP1-AG associated significantly with poorer DFS rates (p = 0.032).

Conclusion: This study demonstrated that GSTT1 _null individually or in combination with GSTM1_null and GSTP1-AG genotypes associated with increased B-ALL risk. Also, rs156697 variant genotypes (AG and GG) associated with B-ALL, whereas the GG genotype of rs156697 influenced the treatment outcome.

Keywords: GSTO1; GSTO2; Kashmir; PCR-RFLP; acute lymphoblastic leukemia; glutathione S-transferase; polymorphism; survival analysis.