Genetic polymorphisms and susceptibility to childhood acute lymphoblastic leukemia

Abstract

Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer. Although exposure to environmental agents appears to predispose individuals to this disease, little attention has been paid to the role of genetic susceptibility to environmental exposures in the etiology of childhood ALL. The enzymes GSTM1, GSTT1, GSTP1, CYP1A1, and CYP2E1 are involved in the bioactivation and detoxification of a variety of xenobiotics present in food, organic solvents, tobacco smoke, drugs, alcoholic drinks, pesticides, and environmental pollutants. Polymorphisms in the genes coding for these enzymes have been associated with increased susceptibility to different cancers, including hematologic malignancies. To investigate whether these polymorphisms represent risk-modifying factors for childhood ALL, a study was conducted involving 113 Brazilian patients of childhood ALL and 221 controls with similar ethnic backgrounds. The data revealed that carriers of the rare GSTP1 Val allele were at higher risk of ALL (odds ratio [OR] = 2.7; 95% confidence interval [CI] = 1.1-6.8; P = 0.04). No difference was found in the prevalence of the GSTM1 and GSTT1 null genotypes between ALL patients and the controls, and no association was found between CYP1A1*2 and CYP2E1*3 variants and ALL. However, when the mutant CYP1A1 and CYP2E1 alleles were considered together with the GSTM1 and GSTP1 risk-elevating genotypes, the risk of ALL was increased further (OR = 10.3; 95% CI = 1.0-111.8; P = 0.05), suggesting a combined effect. These results imply that genetic variants of xenobiotic metabolizing genes influence the risk of developing childhood ALL.

Genetic polymorphisms of NQO1, CYP1A1 and TPMT and susceptibility to acute lymphoblastic leukemia in a Tunisian population

“…The frequency of CYP1A1*2A variant in our control population was estimated at 0.05. This frequency is lower to which reported by other studies [6,7]. The comparison of patients and controls according to CYP1A1*2 variant does not show a statistical significant difference (corrected p value = 0.06).…”

“…It is, however, likely that the risk of ALL from environmental exposure is influenced by co-inheritance of multiple low-risk variants. For example previous case-control studies have shown that variants within cytochrome p4501A1 (CYP1A1), NQO1 or TPMT were associated with increased risk of ALL [6][7][8][9][10].…”

“…In particular, two common polymorphisms, the T6235C change within the 3 0 non-coding region of the gene (CYP1A1*2A, rs464690) and the A4889G change in the heme-binding domain of exon 7 (CYP1A1*2C), have been previously described. The CYP1A1*2A variant was associated with an increasing enzymatic activity and/or inducibility and was one of the most studied polymorphisms in association with leukemia [6,7].…”

Role ofCYP2D6, CYP1A1, CYP2E1, GSTT1, andGSTM1 genes in the susceptibility to acute leukemias

“…CYP1 family enzyme expressions are increased in myeloblastic and lymphoid cell lines, and CYP1 enzymes may contribute to the carcinogenesis of hematopoietic cells [5]. Several groups found that CYP1A1*2 variant allele was not related with childhood acute leukemias [36,52], whereas Sinnett et al showed CYP1A1*2A is one of the significant risk determinants of ALL [31]. Another study from Turkey found homozygous CYP1A1*2A genotype to be under-represented in ALL patients as compared to controls [36].…”

Folate metabolic gene polymorphisms and childhood acute lymphoblastic leukemia: a case–control study

“…1 The known risk factors for childhood leukemia include ionizing radiation, Down's syndrome and monogenic disorders like ataxia telangiectasia. [2][3][4] Both neo-and post-natal exposures and infections have also been suggested to be associated with the disease risk.…”