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Are genotypes of glutathione S-transferase superfamily a risk factor for childhood acute lymphoblastic leukemia? Results of an Italian case–control study

Leukemia volume 21, pages 1122–1124 (2007)Cite this article

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer accounting for approximately 25–30% of all childhood malignancies. Despite much investigation, the causes of the disease are not yet fully understood. Like many other cancers, ALL is considered to be a complex disease determined by a combination of genetic and environmental factors.

The glutathione S-transferase (GST) are a family of detoxifying enzymes involved in the metabolism of numerous environmental carcinogens, it includes several loci with well-characterized polymorphisms. The genes coding for GSTT1 and GSTM1 exhibit a deletion polymorphism that in case of homozygosity leads to the absence of proteins.1 This is a fairly common genotype in humans, with 50% of Caucasians being homozygous for null GSTM1, and 20% homozygous for null GSTT1.2 The GSTP1 gene displays a polymorphism (1578 A>G; NCBI dbSNP: rs1695) that causes a change in amino-acid sequence at codon 105 (Ile105Val) which has been suggested to confer different catalytic activity.3 Conflicting data exist on the association between the risk for childhood ALL and GSTs polymorphism.4 In order to contribute to determine whether GST polymorphism may have any influence on pediatric ALL susceptibility, we study the GSTT1, GSTM1 and GSTP1 genotypes in a large cohort of Italian children with ALL and compared it with that observed in normal controls. All the 509 children (age<18 years) diagnosed with ALL and registered in the AIEOP ALL 95 study between May and December 1996 were considered eligible for this study. Of these patients, 353 (69%) were eligible for genotyping because of the availability of biological material. Controls, all Italian, were chosen among patients admitted to selected institutions because of traumas, acute infectious episodes, or minor surgical procedures. They were matched for sex, age group (0–6; 7–10; 11–18) and area of residence (Northern, Central, Southern Italy and Sardinia). Written informed consent to the study was obtained in accordance with the Helsinki declaration of Principle. Genotyping of leukemic patients was performed on DNA extracted from bone marrow samples taken at diagnosis or, if not available, from samples taken at any time during follow-up. DNA extracted from peripheral blood was used for healthy controls. Genotypes for GSTM1 and GSTT1 were determined according by Chen et al.5 As it is not possible to distinguish between heterozygote and homozygote for GSTM1 and GSTT1, individuals are divided in two groups namely, ‘present’ (with one or two allele) and ‘null’ (both allele deleted); for this reason, we could not calculate if the distribution of GSTT1 and GSTM1 genotypes was in Hardy–Weinberg equilibrium. GSTP1 analysis was performed by evaluating the genotype at codon 105, according to Harries et al.6 This assay subdivides individuals into homozygotes for Ile 105 allele (Ile/Ile), heterozygotes (Ile/Val) and homozygotes for the Val 105 allele (Val/Val). The distributions of GSTP1 genotypes, both in cases and controls were in Hardy-Weinberg equilibrium. The presence of Val allele (Ile/Val and Val/Val) is considered a high-risk genotype. Comparison of frequency distribution between groups was made by means of the χ2 test; the Fischer exact test was used in case of at least one expected frequency less than 5. All tests were two-sided and P-value less than 0.05 has been considered as statistically significant. Crude odds ratios (OR) were also calculated and given with 95% confidence intervals (CI).

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Acknowledgements

This work was supported by Compagnia di S. Paolo; Fondazione CARIGE, ERG S.p.A. We thank Dr Anna Capurro for critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Pediatric Hemato-Oncology, Hematology Unit, G Gasline Children's Hospital, Genova, Italy

    S Pigullo, C Dufour, P Di Michele & M Lanciotti

  2. Epidemiology and Biostatistics Section, Scientific Directorate, G Gaslini Children's Hospital, Genova, Italy

    R Haupt

  3. Section of Medical Statistics, University of Milano-Bicocca, Monza, Italy

    M G Valsecchi

  4. Pediatric Onco-Hematology Clinic, University of Padova, Padova, Italy

    G Basso

  5. Centro Ricerca Tettamanti, Pediatric Clinic, University of Milano-Bicocca, Monza, Italy

    C Rizzari & A Biondi

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  1. S Pigullo
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Correspondence to M Lanciotti.

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Pigullo, S., Haupt, R., Dufour, C. et al. Are genotypes of glutathione S-transferase superfamily a risk factor for childhood acute lymphoblastic leukemia? Results of an Italian case–control study. Leukemia 21, 1122–1124 (2007). https://doi.org/10.1038/sj.leu.2404617

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