Genetic susceptibility to childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. The origin of this disease can be explained by a combination of genetic susceptibility factors and environmental exposures. For the purpose of our study it can be considered as a complex disease, caused by the "carcinogenic" effect of the environment modified by a series of genes. In population, these genes tend to occur in allelic forms representing functional polymorphisms thus explaining inter-individual variability in cancer susceptibility. The latter can be evaluated more realistically in childhood ALL than in sporadic cancers of the adult because of its relatively short latency period. We asked therefore, the question about the role of genes controlling the efficiency of xenobiotics metabolism in childhood leukemogenesis. Xenobiotics (drugs and carcinogens) are excreted from the body after metabolic conversion by enzymes mediating oxidation activation (Phase I) and conjugation detoxificaton (Phase II). Functional variants of these enzymes, resulting from known DNA polymorphisms in the corresponding genes, were shown to influence the risk to a variety of solid tumours in adults. A case-control study on ALL patients and healthy controls in a French-Canadian population was carried out by examining the loci of Phase I, CYP1A1 and CYP2D6, as well as Phase II enzymes, GSTM1, GSTT1, NAT1 and NAT2. The NAT2 slow-acetylator, CYP1A1*2A and GSTM1 null genotypes were shown to be significant risk determinants of ALL (OR=1.6, 1.8 and 1.8, respectively), whereas, polymorphisms in CYP2D6 and GSTT1 genes did not seem to play an important role in the aetiology of ALL. Interestingly, the risk associated with NAT2 slow-acetylators was most apparent among males homozygous for NAT1*4 (OR=3.3) whereas girls carrying the CYP1A1*4 allele were significantly underrepresented in the patient group (OR=0.2). These findings point to a gender-specific effect of DNA variants which, at least in part, may explain why ALL is more prevalent among boys. To assess gene-gene interactions, NAT2 slow-acetylators were considered together with GSTM1 null genotypes and CYP1A1*2A alleles. The combined presence of two risk-elevating genotypes appeared to confer an increased risk of ALL among the carriers (OR=2.6). This risk was increased further (OR=3.3) when all three genotypes occurred in the same individuals indicating that the combination of susceptibility variants is more predictive of risk then either of them independently. The association of leukemogenesis in children with metabolising gene variants suggests causal relation to environmental exposures.