title: Profile of polymorphisms of drug-metabolising enzymes and the risk of therapy-related leukaemia.
abstract: Therapy-related acute myeloid leukaemia/myelodysplastic syndrome (t-AML/t-MDS) results from an impaired ability to detoxify chemotherapeutic drugs or repair drug-induced genetic damage caused by genetic polymorphisms in enzymes involved in the metabolism of drugs. We analysed the prevalence of genetic polymorphisms of CYP1A1*2A(T6235C), CYP2E1*5B(C-1019T), CYP3A4*1B(A-290G), del{GSTT1}, del{GSTM1}, NQO1*2(C609T), MTHFR(C677T) and TYMS 2R/3R in 78 t-AML/t-MDS and 458 normal individuals (control group, CG) using real-time and conventional polymerase chain reaction (PCR)-based methods. The incidences of polymorphisms among t-AML/t-MDS patients and CG individuals were similar. However, a polymorphism profile consisting of CYP1A1*2A, del{GSTT1} and NQO1*2 strongly modified the risk of t-AML/t-MDS. The absence of all three polymorphisms decreased the risk of t-AML/t-MDS 18-fold (odds ratio (OR) = 0.054, 95% confidence interval (CI) = 0.005-0.63, P = 0.02), whereas the presence of only NQO1*2 or all three polymorphisms enhanced the risk of t-AML/t-MDS (OR = 2.09, 95% CI = 1.08-4.03, P = 0.03 and OR = 18.42, 95% CI = 1.59-212.76, P = 0.02 respectively). Thus, the profiles of genetic polymorphisms of drug-metabolising enzymes might explain the increased risk to t-AML/t-MDS observed in some patients treated with polychemotherapy.
authors: Laboratory of Molecular Biology (Medical Biopathology), Hospital Universitario La Fe, Valencia, Spain. bolufer_pas@gva.es
authors: Pascual
authors: P
authors: Bolufer
authors: Maria
authors: M
authors: Collado
authors: Eva
authors: E
authors: Barragan
authors: María-José
authors: MJ
authors: Calasanz
authors: Dolors
authors: D
authors: Colomer
authors: Mar
authors: M
authors: Tormo
authors: Marcos
authors: M
authors: González
authors: Salut
authors: S
authors: Brunet
authors: Montserrat
authors: M
authors: Batlle
authors: José
authors: J
authors: Cervera
authors: Miguel-Angel
authors: MA
authors: Sanz
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D007223:Infant; D007951:Leukemia, Myeloid / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D011110:Polymorphism, Genetic; D012189:Retrospective Studies
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D019363:Cytochrome P-450 CYP1A1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C413545:glutathione S-transferase T1; D005982:Glutathione Transferase