CC BY-NC-ND 4.0 · Indian J Med Paediatr Oncol 2011; 32(01): 25-29
DOI: 10.4103/0971-5851.81886
ORIGINAL ARTICLE

Role of glutathione-s-transferase and CYP1A1FNx012A polymorphisms in the therapy outcome of south Indian acute lymphoblastic leukemia patients

K J Suneetha
Department of Molecular Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
,
K Nirmala Nancy
Department of Molecular Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
,
K R Rajalekshmy
Department of Hematology & Immunology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
,
R Rama
Department of Biostatistics & Tumor Registry, Cancer Institute (WIA), Chennai, Tamil Nadu, India
,
T G Sagar
Department of Medical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
,
T Rajkumar
Department of Molecular Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
› Author Affiliations
Source of Support DST (DST No. SR/SO/HS-26/2004)

Abstract

Background: Polymorphisms in the drug-metabolizing enzymes are found to be associated with the inter-individual variation in response to a particular drug. Glutathione S-transferases (GSTs) are involved in the metabolism of several anticancer drugs, including alkylating agents, anthracyclines, and cyclophosphamides. Aim: The present study is aimed to examine the association of GST and CYP1A1FNx012A polymorphisms in the susceptibility to acute lymphoblastic leukemia (ALL) and the prognostic significance. Materials and Methods: A total of 92 immunophenotyped patients and 150 cord blood controls were genotyped by PCR for GSTM1 and GSTT1, RQ-PCR allelic discrimination assay for GSTP1 and PCR-RFLP for CYP1A1FNx012A polymorphism. Results: We have previously reported the significant association of GSTM1 (null) and combined GSTP1 {(Ile/Val)/ (Val/Val)} /GSTM1 (null) genotype with the susceptibility to ALL. No significant association was observed with GSTT1 (P=0.75) and CYP1A1FNx012A (P=0.61 for +/- and P=0.86 for -/- respectively) in the susceptibility to ALL. Survival analysis was performed in 50 of the 92 patients who were followed for three years. Kaplan-Meier survival analysis for three years showed significant lower event-free survival in patients harboring GSTP1 (Ile/Val) and GSTP1 (Val/Val) (P=0.038 and 0.0001, respectively) genotype. Cox regression analysis revealed GSTP1 as an independent prognostic marker with 6-fold higher risk with Val/Val genotype (P=0.003). Conclusions: Our results show that GSTP1 (Ile/Val) polymorphism has a role in the susceptibility to ALL and also influence treatment outcome.



Publication History

Article published online:
16 August 2021

© 2011. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

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  • References

  • 1 Stanulla M, Schrappe M, Brechlin AM, Zimmermann M, Welte K. Polymorphisms within glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia: A case-control study. Blood 2000;95:1222-8.
  • 2 Krajinovic M, Labuda D, Richer C, Karimi S, Sinnett D. Susceptibility to childhood acute lymphoblastic leukemia: Influence of CYP1A1, CYP2D6, GSTM1 and GSTT1 genetic polymorphisms. Blood 1999;93:1496-501.
  • 3 Kellen E, Hemelt M, Broberg K, Golka K, Kristensen VN, Hung RJ, et al. Pooled analysis and meta-analysis of the glutathione S-transferase P1 Ile 105Val polymorphism and bladder cancer: A HuGE-GSEC review. Am J Epidemiol 2007;165:1221-30.
  • 4 Ryberg D, Skaug V, Hewer A, Phillips DH, Harries LW, Wolf CR, et al. Genotypes of glutathione transferase M1 and P1 and their significance for lung DNA adduct levels and cancer risk. Carcinogenesis 1997;18:1285-9.
  • 5 White DL, Li D, Nurgalieva Z, El-Serag HB. Genetic variants of glutathione S-transferase as possible risk factors for hepatocellular carcinoma: A HuGE systematic review and meta-analysis. Am J Epidemiol 2008;167:377-89.
  • 6 Ntais C, Polycarpou A, Ioannidis JP. Association of GSTM1, GSTT1 and GSTP1 gene polymorphisms with the risk of prostate cancer: A meta-analysis. Cancer Epidemiol Biomarkers Prev 2005;14:176-81.
  • 7 Sundberg K, Johansson AS, Stenberg G, Widersten M, Seidel A, Mannervik B, et al. Differences in the catalytic efficiencies of allelic variants of glutathione transferase P1-1 towards carcinogenic diol epoxides of polycyclic aromatic hydrocarbons. Carcinogenesis 1998;19:433-6.
  • 8 Hu X, Xia H, Srivastava SK, Pal A, Awasthi YC, Zimniak P, et al. Catalytic efficiencies of allelic variants of human glutathione S-transferase Pl-1 toward carcinogenic anti-diol epoxides of benzo[c]phenanthrene and benzo[g]chrysene. Cancer Res 1998;58:5340-3.
  • 9 Masson LF, Sharp L, Cotton SC, Little J. Cytochrome P-450 1A1 gene polymorphisms and risk of breast cancer: A HuGE review. Am J Epidemiol 2005;161:901-15.
  • 10 Georgiadis P, Topinka J, Vlachodimitropoulos D, Stoikidou M, Gioka M, Stephanou G, et al. Interactions between CYP1A1 polymorphisms and exposure to environmental tobacco smoke in the modulation of lymphocyte bulky DNA adducts and chromosomal aberrations. Carcinogenesis 2005;26:93-101.
  • 11 Alves S, Amorim A, Ferreira F, Norton L, Prata MJ. The GSTM1 and GSTT1 genetic polymorphisms and susceptibility to acute lymphoblastic leukemia in children from north Portugal. Leukemia 2002;16:1565-7.
  • 12 Balta G, Yuksek N, Ozyurek E, Ertem U, Hicsonmez G, Altay C, et al. Characterization of MTHFR, GSTM1, GSTP1 and CYP1A1 genotypes in childhood acute leukemia. Am J Hematol 2003;73:154-60.
  • 13 Bolufer P, Collado M, Barragan E, Cervera J, Calasanz MJ, Colomer D, et al. The potential effect of gender in combination with common genetic polymorphisms of drug-metabolizing enzymes on the risk of developing acute leukaemia. Haematologica 2007;92:308-14.
  • 14 Chen CL, Liu Q, Pui CH, Rivera GK, Sandlund JT, Ribeiro R, et al. Higher frequency of glutathione S-transferase deletions in black children with acute lymphoblastic leukemia. Blood 1997;89:1701-7.
  • 15 Gallegos-Arreola MP, González-García JR, Figuera LE, Puebla-Pérez AM, Delgado-Lamas JL, Zúñiga-González GM. Distribution of CYP1A1FNx012A polymorphism in adult patients with acute lymphoblastic leukemia in a Mexican population. Blood Cells Mol Dis 2008;41:91-4.
  • 16 Krajinovic M, Labuda D, Mathonnet G, Labuda M, Moghrabi A, Champagne J, et al. Polymorphisms in genes encoding drugs and xenobiotic metabolizing enzymes, DNA repair enzymes, and response to treatment of childhood acute lymphoblastic leukemia. Clin Cancer Res 2002;8:802-10.
  • 17 Haranatha RP, Kaiser J. Polymorphisms in the GST (M1 and T1) gene and their possible association with susceptibility to childhood acute lymphocytic leukemia in Indian population. Afr J Biotechnol 2006;5:1454-6.
  • 18 Joseph T, Kusumakumary P, Chacko P, Abraham A, Radhakrishna Pillai M. Genetic polymorphism of CYP1A1, CYP2D6, GSTM1 and GSTT1 and susceptibility to acute lymphoblastic leukaemia in Indian children. Pediatr Blood Cancer 2004;43:560-7.
  • 19 Pakakasama S, Mukda E, Sasanakul W, Kadegasem P, Udomsubpayakul U, Thithapandha A, et al. Polymorphisms of drug-metabolizing enzymes and risk of childhood acute lymphoblastic leukemia. Am J Hematol 2005;79:202-5.
  • 20 Suneetha KJ, Nancy KN, Rajalekshmy KR, Sagar TG, Rajkumar T. Role of GSTM1 (Present/Null) and GSTP1 (Ile105Val) polymorphisms in susceptibility to acute lymphoblastic leukemia among the South Indian population. Asian Pac J Cancer Prev 2008;9:733-6.
  • 21 Shanta V, Maitreyan V, Sagar TG, Gajalakshmi CK, Rajalekshmy KR. Prognostic variables and survival in pediatric acute lymphoblastic leukemia:Cancer institute experience. Pediatr Hematol Oncol 1996;13:205-16.
  • 22 Möricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, Gadner H. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia 2010;24:265-84.
  • 23 Davies SM, Bhatia S, Ross JA, Kiffmeyer WR, Gaynon PS, Radloff GA, et al. Glutathione S transferase genotypes, genetic susceptibility and outcome of therapy in childhood acute lymphoblastic leukemia. Blood 2002;100:67-71.
  • 24 Rollinson S, Roddam P, Kane E, Roman E, Cartwright R, Jack A, et al. Polymorphic variation within the glutathione-S-transferase genes and risk of adult acute leukemia. Carcinogenesis 2002;21:43-7.
  • 25 Stanulla M, Schäffeler E, Arens S, Rathmann A, Schrauder A, Welte K, et al. GSTP1 and MDR1 genotypes and central nervous system relapse in childhood acute lymphoblastic leukemia. Int J Hematol 2005;81:39-44.
  • 26 Tew KD. Glutathione-associated enzymes in anticancer drug resistance. Cancer Res 1994;54:4313-20.
  • 27 Kearns PR, Pieters R, Rottier MM, Pearson AD, Hall AG. Raised blast glutathione levels are associated with an increased risk of relapse in childhood acute lymphocytic leukemia. Blood 2001;97:393-8.
  • 28 Noelle RJ, Lawrence DA. Determination of glutathione in lymphocytes and possible association of redox state and proliferative capacity of lymphocytes. Biochem J 1981;198:571-9.
  • 29 Moureau-Zabotto L, Ricci S, Lefranc JP, Coulet F, Genestie C, Antoine M, et al. Prognostic impact of multidrug resistance gene expression on the management of breast cancer in the context of adjuvant therapy based on a series of 171 patients. Br J Cancer 2006;94:473-80.
  • 30 Lee JM, Wu MT, Lee YC, Yang SY, Chen JS, Hsu HH, et al. Association of GSTP1 polymorphism and survival for esophageal cancer. Clin Cancer Res 2005;11:4749-53.
  • 31 Rocha JC, Cheng C, Liu W, Kishi S, Das S, Cook EH, et al. Pharmacogenetics of outcome in children with acute lymphoblastic leukemia. Blood 2005;105:4752-8.