title: Decreased survival in normal karyotype AML with single-nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5'-nucleotidase.
abstract: De novo acute myeloid leukemia with normal karyotype (NK-AML) comprises a large group of patients with no common cytogenetic alterations and with a large variation in treatment response. Single-nucleotide polymorphisms (SNPs) in genes related to the metabolism of the nucleoside analogue AraC, the backbone in AML treatment, might affect drug sensitivity and treatment outcome. Therefore, SNPs may serve as prognostic biomarkers aiding clinicians in individualized treatment decisions, with the aim of improving patient outcomes. We analyzed polymorphisms in genes encoding cytidine deaminase (CDA 79A>C rs2072671 and -451C>T rs532545), 5'-nucleotidase (cN-II 7A>G rs10883841), and deoxycytidine kinase (DCK 3'UTR 948T>C rs4643786) in 205 de novo NK-AML patients. In FLT3-internal tandem duplication (ITD)-positive patients, the CDA 79C/C and -451T/T genotypes were associated with shorter overall survival compared to other genotypes (5 vs. 24 months, P < 0.001 and 5 vs. 23 months, P = 0.015, respectively), and this was most pronounced in FLT3-ITD-positive/NPM1-positive patients. We observed altered in vitro sensitivity to topoisomerase inhibitory drugs, but not to nucleoside analogues, and a decrease in global DNA methylation in cells carrying both CDA variant alleles. A shorter survival was also observed for the cN-II variant allele, but only in FLT3-ITD-negative patients (25 vs. 31 months, P = 0.075). Our results indicate that polymorphisms in genes related to nucleoside analog drug metabolism may serve as prognostic markers in de novo NK-AML.
authors.affiliation: Clinical Pharmacology, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Ingrid Jakobsen
authors.initials: IJ
authors.lastname: Falk
authors.forename: Anna
authors.initials: A
authors.lastname: Fyrberg
authors.forename: Esbjörn
authors.initials: E
authors.lastname: Paul
authors.forename: Hareth
authors.initials: H
authors.lastname: Nahi
authors.forename: Monica
authors.initials: M
authors.lastname: Hermanson
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.forename: Martin
authors.initials: M
authors.lastname: Höglund
authors.forename: Lars
authors.initials: L
authors.lastname: Palmqvist
authors.forename: Dick
authors.initials: D
authors.lastname: Stockelberg
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wei
authors.forename: Henrik
authors.initials: H
authors.lastname: Gréen
authors.forename: Kourosh
authors.initials: K
authors.lastname: Lotfi
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003131:Combined Modality Therapy; D003561:Cytarabine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003564:Cytidine Deaminase / Q000235:genetics*; D019175:DNA Methylation; D003630:Daunorubicin / Q000008:administration & dosage; D003842:Deoxycytidine Kinase / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage; D008658:Inactivation, Metabolic / Q000235:genetics; D053208:Kaplan-Meier Estimate; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000401:mortality* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D016019:Survival Analysis; D020080:Tandem Repeat Sequences; D059004:Topoisomerase I Inhibitors / Q000493:pharmacokinetics; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D000964:Antimetabolites, Antineoplastic; C000716967:NPM1 protein, human; D009363:Neoplasm Proteins; D059004:Topoisomerase I Inhibitors; D003561:Cytarabine; D000090243:Nucleophosmin; D003842:Deoxycytidine Kinase; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D015720:5'-Nucleotidase; C508048:NT5C2 protein, human; D003564:Cytidine Deaminase; D015255:Idarubicin; D003630:Daunorubicin