Pharmacogenomics and the Treatment of Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is a clinically and biologically heterogeneous malignancy that is primarily treated with combinations of cytarabine and anthracyclines. Although this scheme remains effective in most of the patients, variability of outcomes in patients has been partly related with their genetic variability. Several pharmacogenetic studies have analyzed the impact of polymorphisms in genes encoding transporters, metabolizers or molecular targets of chemotherapy agents. A systematic review on all eligible studies was carried out in order to estimate the effect of polymorphisms of anthracyclines and cytarabine pathways on efficacy and toxicity of AML treatment. Other emerging genes recently studied in AML, such as DNA repair genes, genes potentially related to chemotherapy response or AML prognosis, have also been included.

Polymorphisms at microRNA binding sites of Ara-C and anthracyclines-metabolic pathway genes are associated with outcome of acute myeloid leukemia patients

“…In this study, we selected a total of 20 key candidate genes described in pervious studies [ 14 – 16 ] are directly related to the pharmacokinetic and/or pharmacodynamics pathways of Ara-C and anthracycline, i.e., 10 Ara-C associated genes (Deoxycytidine kinase , DCK ; Cytidine deaminase , CDA ; human equilibrative nucleoside transporter, hENT1 / SLC29A1 ; Solute carrier family 28 member, SLC28A3, SLC28A1 ; 5′ nucleotidase 3 , NT5C3 ; 5′ nucleotidase 2, NT5C2 ; Deoxycytidylate deaminase , DCTD ; Ribonucleotide reductase , RRM1 and RRM2 ) and 10 anthracycline-associated genes (ATP binding cassette subfamily A, B, C, G member, ABCA3 , ABCB1 , ABCC1 , ABCG2, ABCC10, ABCC11 ; Glutathione S-transferase, GSTM1, GSTT1 , Carbonyl reductases, C BR3, and CBR1 ). We then utilized tools in the SNPinfo Web Server to identify putative SNPs in 3′-UTR with potential miRNA-binding sites.…”

Prognostic markers in acute myeloid leukemia : A candidate gene approach

“…Generally, the ABCB1 SNP research area has provided conflicting results regarding impact on expression, function and/or clinical consequences (40)(41)(42)(43)(44)(45)(46)(47)(48). A recent meta-analysis showed significant influence of 1236C>T, 2677G>T/A and 3435C>T on overall survival in AML patients with standard chemotherapy (49), an analysis partly based on the results of the work in this thesis.…”

“…Two more recent meta-analyses also report associations between ABCB1 SNPs and overall survival in AML with standard induction treatment (49,115). Our Paper I and Paper III were included as part of the meta-analyses (a total of seven publications met the inclusion criteria), and concluded that there was a positive influence of all the three abovementioned SNPs and OS as well as CR.…”

Association of PARP1 polymorphisms with response to chemotherapy in patients with high‐risk neuroblastoma

“…The way in which a cancer patient responds to drug treatment is dependent on many variables and among these, the individual genotype is an essential factor for influencing drug behaviour. Because of the importance of DNA repair process in determining drug sensitivity and resistance, in various cancer types, the role of polymorphisms in DNA repair genes have been explored to explain inter‐individual differences in the treatment response or survival . Many studies focused their attention on the role of PARP1 polymorphisms and their relation with increased risk for various cancer types .…”