Genetic polymorphism of NAD(P)H:quinone oxidoreductase is associated with an increased risk of infant acute lymphoblastic leukemia without MLL gene rearrangements

Abstract

NAD(P)H:quinone oxidoreductase 1 (NQO1) is a detoxification enzyme that protects cells against oxidative stress and toxic quinones. A polymorphism (C609T) in the gene produces in the heterozygous individuals (C/T) a reduction and in those homozygous for the variant allele (T/T) the abolishment of NQO1 protein activity. To assess whether NQO1 inactivating polymorphism (CT/TT) was a possible risk factor for infant acute lymphoblastic leukemia (iALL), we investigated the distribution of NQO1 genotype in 50 iALL patients, 32 with MLL gene rearrangements (MLL þ ) and 18 without (MLLÀ). As controls, 106 cases of pediatric ALL (pALL), and 147 healthy subjects were also studied. Compared to normal controls, the frequency of the low/null activity NQO1 genotypes was significantly higher in the iALL MLLÀ (72 vs 38%, P ¼ 0.006; odds ratio (OR) 4.22, 95% confidence interval (CI) 1.43-12.49), while no differences were observed in iALL MLL þ (44 vs 38%, P ¼ 0.553; OR 1.26, 95% CI 0.58-2.74). Similar results were observed when pALL were used as control. Our results indicate that only the iALL patients without MLL rearrangements had a significantly higher frequency of NQO1 genotypes associated with low/null activity enzyme, suggesting a possible role for NQO1 gene as an MLL-independent risk factor, in the leukemogenic process of this subtype of iALL.

The potential effect of gender in combination with common genetic polymorphisms of drug-metabolizing enzymes on the risk of developing acute leukemia

“…Thus, the presence of the NQO1*2 polymorphism increased the risk of ALL only in males, but did not modify it in females. The increased risk of ALL conferred by NQO1*2 homozygosity found in this study is in agreement with some studies carried out in children with ALL; [31][32][33] however, other reports did not support these results.…”

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

“…In this context others studies have examined the NQO1*2 distribution according to MLL rearrangement status and have produced conflicting result. While Lanciotti et al [8] indicate that only the infantile ALL patients without MLL rearrangements had a significantly higher frequency of NQO1 genotypes associated with low/null activity enzyme. Wiemels et al [41] have found that low NQO1 activity genotypes (heterozygous CT or homozygous TT) were associated with ALL containing the MLL gene rearrangements.…”

“…This results in a proline to serine amino acid change at codon 187 that is associated with a loss of enzyme activity due to instability of the protein product. The NQO1*2 is associated with an increased risk of tobacco-related cancers and ALL [8,9,17,18]. Moreover other polymorphisms were detected in NQO1 gene and were associated with the modification of the enzyme activity like the NQO1*3.…”

“…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].…”

Childhood cancer epidemiology in low‐income countries

“…14,15 Some other cases of childhood ALL can be attributed to maternal exposures during pregnancy, 16,17 in which risk may be modulated by genetic polymorphisms of enzyme systems responsible for the metabolism of drugs or environmental xenobiotics. [18][19][20][21] However, variations in environmental exposures and genetic susceptibility can only account for small differences in childhood leukemia incidence rates, and do not explain the large differences (up to 10-fold) between HIC and some LIC (Table 2). Hence, the role of underdiagnosis and underreporting must be investigated.…”