Combined interaction of multi-locus genetic polymorphisms in cytarabine arabinoside metabolic pathway on clinical outcomes in adult acute myeloid leukaemia (AML) patients

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

“…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]. Previous study found that rs329491 of SLC29A1 maybe a favorable survival factor for patients with pancreatic cancer [34].…”

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

“…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]. Nevertheless, few studies have determined SNP functions, and it is possible that CDA rs2072671 caused CDA protein variants (p.Lys27Gln) that may be related to the loss of CDA activity [31].…”

“…In one such study, Gamazon et al [11] conducted a meta-analysis of genome-wide association studies involving 523 lymphoblastoid cell lines from individuals of European, African, Asian, and African American ancestry, and identified 18 of 33 SNPs associated with either cytarabine 50 % inhibitory concentration in leukemia cells or clinical response parameters among patients randomized to receive low-dose or high-dose Ara-C plus daunorubicin and etoposide. In addition, Kim et al [13] reported that the SLC29A1 rs3734703 AA/AC genotype in combination with TYMS rs2612100 AA genotype was significantly associated with shorter relapse-free survival in Korean AML patients received an induction regimen of Ara-C and idarubicin followed by sequential consolidation therapy with Ara-C and anthracyclines or hematopoietic stem cell transplantation (HSCT). However, in these reports, the patient background included anthracycline agents or HSCT and thus might not accurately reflect the influence of genetic polymorphism on Ara-C metabolism.…”

“…Indeed, each of the Ara-C metabolism-associated genes exhibits a significant degree of genetic variation, particularly via single nucleotide polymorphisms (SNPs), and several studies of individual SNPs in Ara-C metabolic genes have reported that genetic background plays an important role in the clinical outcomes of AML patients receiving Ara-C-based therapy [11][12][13]. In one such study, Gamazon et al [11] conducted a meta-analysis of genome-wide association studies involving 523 lymphoblastoid cell lines from individuals of European, African, Asian, and African American ancestry, and identified 18 of 33 SNPs associated with either cytarabine 50 % inhibitory concentration in leukemia cells or clinical response parameters among patients randomized to receive low-dose or high-dose Ara-C plus daunorubicin and etoposide.…”

Using Pharmacogene Polymorphism Panels to Detect Germline Pharmacodynamic Markers in Oncology

“…Another custom Goldengate panel was used to assess 139 SNPs in 10 genes relevant to cytosine arabinoside (Ara-C) transport and metabolism (54). After multiple comparisons, correction, and adjustment for relevant prognostic factors one SNP in DCK (rs4694362) was associated with overall survival [HR ¼ 33.20 (4.94-223.27), Bonferroniadjusted P ¼ 0.017], and an interaction between SNPs in SLC29A1 and TYMS was associated with relapse-free survival [HR ¼ 17.63 (4.83-63.47), Bonferroni-adjusted P ¼ 0.021] in 97 patients with AML.…”