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Polymorphisms in Genes Encoding Drugs and Xenobiotic Metabolizing Enzymes, DNA Repair Enzymes, and Response to Treatment of Childhood Acute Lymphoblastic Leukemia¹

Service d’Hématologie-Oncologie, Centre de Recherche, Hôpital Sainte-Justine [M. K., D. L., G. M., M. L., A. M., J. C., D. S.], and Département de Pédiatrie, Université de Montréal [M. K., D. L., A. M., J. C., D. S.], Montréal, Quebec, H3T 1C5 Canada

Purpose: The most common childhood malignancy, acute lymphoblastic leukemia (ALL), remains the leading cause of cancer-related death in children because of resistant cases in which underlying predisposing factors are poorly understood. The interindividual variation in the activity of xenobiotic metabolizing enzymes that modify individual somatic mutation burden in the context of environmental exposure was shown to modify susceptibility to childhood ALL. Variable DNA repair capacity may further modulate induced DNA lesions. Similarly, differential capacity of ALL patients to process carcinogens and chemotherapeutic drugs could both modify an individual’s risk of recurrent malignancy and response to therapy.

Experimental Design: We investigated the relationship between the risk of relapse in ALL patients and functional polymorphisms in genes encoding carcinogen-metabolizing enzymes, including CYP1A1, CYP2D6, CYP2E1, MPO, GSTM1, GSTT1, GSTP1, NAT1, NAT2, NQO1, as well as DNA-repair enzymes hMLH1, hMSH3, XRCC1, XPF, and APE. Our study included 320 children with ALL, of which 68 relapsed or died because of this disease within 5 years of follow-up.

Results: Among children of the latter group, we found that carriers of CYP1A1*2A and NQO1*2 variants had worse disease prognosis according to Kaplan-Meier (P = 0.003) and Cox regression (P 0.03) analyses. hMLH1 Ile219 contributed to the increased risk of relapse when combined with the CYP1A1*2A variant.

Conclusions: Our findings suggest that determining individual genotypes can become important in predicting disease outcome. Genotyping could also guide the therapeutic protocol.

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