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. Singlenucleotide 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 2451C>T rs532545), 5 0 -nucleotidase (cN-II 7A>G rs10883841), and deoxycytidine kinase (DCK 3 0 UTR 948T>C rs4643786) in 205 de novo NK-AML patients. In FLT3-internal tandem duplication (ITD)-positive patients, the CDA 79C/C and 2451T/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 5 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 5 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. Am. J. Hematol. 88:1001Hematol. 88: -1006Hematol. 88: , 2013. V C 2013 Wiley Periodicals, Inc. IntroductionAcute myeloid leukemia (AML) is characterized by failed differentiation and uncontrolled proliferation of hematopoietic myeloid progenitor cells. With modern treatments, the majority of patients with AML obtain a complete remission (CR), but more than two-third of adult AML patients relapse and the 5-year survival rate is only 30-40%; <15% in patients above the age of 60 [1]. The most common treatment for AML currently in use is a combination of the nucleoside analog cytosine arabinoside (AraC) and an anthracycline such as daunorubicin or idarubicin, followed by consolidation chemotherapy and/or stem cell transplantation.Cytogenetic characterization of AML at diagnosis is crucial for treatment strategies and prognosis. Based on cytogenetic aberrations, patients can be stratified into high-, intermediate-, and low-risk patient groups [2,3]. However, almost half of the AML patients do not show any cytogenetic aberrations and are referred to as normal karyotype AML (NK-AML) [2]. Patients (<70 years) in this group have a 5-year overall survival (OS) of 35-40%, but this intermediate-risk group is very heterogeneous with respect to treatment response and risk of relapse [4].A number of mutations are known to predict response and outcome in the NK-AML group [5,6]. The fms-like tyrosine kinase 3 (FLT3) gene is mutated and constitutively active in about 30% of the AML patients, the m...

SLC29A1 single nucleotide polymorphisms as independent prognostic predictors for survival of patients with acute myeloid leukemia: an in vitro study

“…Decreased Ara-C transport over the cell membrane into the cytoplasm [6,22] or inactivation of DCK [23,24] can both offset the cytotoxic function of Ara-C. Our previous study showed continuous exposure to Ara-C could induce drug resistance with decreased transcription level of DCK and SLC29A1 as well as elevated mRNA expression of CDA (data not shown). Genetic variations, particularly SNPs, have been identified in these genes involved in Ara-C transport and metabolism [25][26][27]. Both in vivo and in vitro studies demonstrated that the activities of these enzymes are correlated with polymorphic gene variations [28,29], and some of these SNPs are even highly correlated with treatment response and survival of AML patients with Ara-C based chemotherapy [30][31][32][33].…”

Single nucleotide polymorphisms of cytarabine metabolic genes influence clinical outcome in acute myeloid leukemia patients receiving high-dose cytarabine therapy

“…RRM1 rs1042919 and rs1561876 were related to intracellular Ara-CTP concentration, CR rate, and OS [29]. CDA rs2072671 and rs532545 were related to OS in a FLT3-ITD mutation-positive normal karyotype AML patient, and NT5C2 rs10883841 was related to OS in a FLT3-ITD mutationnegative case [30]. In addition, the SLC29A1 rs3734703 AA/AC genotype in combination with TYMS rs2612100 was significantly associated with relapse-free survival and DCK rs469436 was associated with OS in AML patients [13].…”

Determinants of the interindividual variability in serum cytidine deaminase activity of patients with solid tumours

“…A large interindividual variability in serum CDA activity has been reported . The determination of CDA gene polymorphisms has shown promising but discrepant results with regards to their correlation with serum CDA activity and clinical activity of nucleoside analogues . This discrepancy between serum enzyme activity and CDA gene polymorphisms suggests that other factors are likely to contribute to the large interindividual variability in serum CDA activity.…”