1543

CYP1A1

AHH|AHRR|CP11|CYP1|P1-450|P450-C|P450DX;cytochrome P450, family 1, subfamily A, polypeptide 1;CYP1A1;cytochrome P450, family 1, subfamily A, polypeptide 1

CYPIA1|aryl hydrocarbon hydroxylase|cytochrome P1-450, dioxin-inducible|cytochrome P450 1A1|cytochrome P450 form 6|cytochrome P450, subfamily I (aromatic compound-inducible), polypeptide 1|cytochrome P450-C|cytochrome P450-P1|flavoprotein-linked monooxyge

15q24.1

protein-coding

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 studyit 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 oxidationactivation (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. TheNAT2 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 ofrisk then either of them independently. The association of leukemogenesis in children with metabolising gene variants suggests causal relation to environmental exposures.

BACKGROUND: Biotransformation plays a crucial role in carcinogen activity and many genetic polymorphisms in xenobiotic metabolising enzymes have been associated with an increased risk of cancer. Such polymorphisms can lead to considerable variation in the activities of these enzymes, which are crucial in carcinogen and drug metabolism. These variations could play a role in the risk of developing paediatric acute lymphoblastic leukaemia (ALL) by their varying action on environmental carcinogens. PROCEDURE: The present study looked for two polymorphisms (m1 and m2) in the CYP1A1, CYP2D6*4 genes and deletions of the glutathione S-transferases (GSTM1 and GSTT1) in 118 paediatric ALL patients and 118 age matched control children. The polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used to study gene polymorphisms. RESULTS: In children with ALL, CYP1A1 m1 polymorphism was evidentin 42.4% of subjects and CYP1A1 m2 in 37.3%. These were significantly different from the results obtained for control children (20.3% for CYP1A1 m1 and 19.5% for m2). Subjects with CYP1A1 m1 homozygous variant had a sixfold risk and CYP1A1 m2a fourfold risk. In contrast, CYP2D6*4 was more prevalent in the controls than in the cases. Subjects with GSTM1 deletions had increased risk of ALL (OR = 2.1, P = 0.009). The odds ratios for both CYP1A1 m1 and m2 homozygous polymorphisms beingassociated with childhood ALL was 5.67 (95% CI = 2.11-15.27). The odds ratios for both GSTM1 and GSTT1 deletions being associated with ALL was 2.78 (95% CI = 0.67-11.56). CONCLUSIONS: These results suggest that genetic polymorphisms of xenobiotic metabolising enzymes appear to influence susceptibility to childhood ALL.#CI- Copyright 2004 Wiley-Liss, Inc.