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Randomized Controlled Trial
. 2014 Nov 15;33(1):90.
doi: 10.1186/s13046-014-0090-9.

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

Haixia Wan  1 , Jianyi Zhu  2 , Fangyuan Chen  3 , Fei Xiao  4 , Honghui Huang  5 , Xiaofeng Han  6 , Lu Zhong  7 , Hua Zhong  8 , Lan Xu  9 , Beiwen Ni  10 , Jihua Zhong  11
Affiliations
Randomized Controlled Trial

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

Haixia Wan et al. J Exp Clin Cancer Res. .

Abstract

Background: The mechanism behind poor survival of acute myeloid leukemia (AML) patients with 1-barabinofuranosylcytosine (Ara-C) based treatment remains unclear. This study aimed to assess the pharmacogenomic effects of Ara-C metabolic pathway in patients with AML.

Methods: The genotypes of 19 single nucleotide polymorphisms (SNPs) of DCK, CDA and SLC29A1from 100 AML patients treated with Ara-C were examined. All the SNPs were screened with ligase detection reaction assay. The transcription analysis of genes was examined by quantitative real time polymerase chain reaction. The association between clinical outcome and gene variants was evaluated by Kaplan-Meier method.

Results: Genotypes of rs9394992 and rs324148 for SLC29A1 in remission patients were significantly different from those in relapsed ones. Post-induction overall survival (OS) significantly decreased in patients with the CC genotype of rs324148 compared with CT and TT genotypes (hazard ratio [HR] = 2.997 [95% confidence interval (CI): 1.71-5.27]). As compared with CT and TT genotype, patients with the CC genotype of rs9394992 had longer survival time (HR = 0.25 [95% CI: 0.075-0.81]; HR = 0.43 [95% CI: 0.24-0.78]) and longer disease-free survival (DFS) (HR = 0.52 [95% CI: 0.29-0.93]; HR = 0.15 [95% CI: 0.05-0.47]) as well As compared with CT and TT genotype, patients with the CC genotype of rs324148 had shorter DFS (HR = 3.18 [95% CI: 1.76-5.76]). Additionally, patients with adverse karyotypes had shorter DFS (HR = 0.17 [95% CI: 0.05-0.54]) and OS (HR = 0.18 [95% CI: 0.05-0.68]).

Conclusions: AML patients with low activity of SLC29A1 genotype have shorter DFS and OS in Ara-C based therapy. Genotypes of rs9394992 and rs324148 may be independent prognostic predictors for the survival of AML patients.

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Figures

Figure 1
Figure 1
Schematic description of Ara-C transport and metabolism. The asterisked letters indicate genes examined in this study.
Figure 2
Figure 2
The mRNA expression of genes related to Ara-C efficacy in AML. Gene expression levels of DCK, CDA, and SLC29A1 were analyzed by quantitative RT-PCR. β-actin was used as an internal control. *#$ indicated statistically significant (P < 0.05).
Figure 3
Figure 3
SLC29A1 Haplotype structure. The haplotype structure of SLC29A1 was generated based on HapMap Phase II + III Release 27 data. Colors ranging from bright red to light red to white indicate the range of r2 values from high to low. The link of rs9394992 to rs324148 that we identified in the survival analysis for AML patients is in the white (a) or light red box (b) with r2 < 0.5. CHB: Han Chinese in Beijing, China. CEU: Utah residents with Northern and Western European ancestry from CEPH collection.
Figure 4
Figure 4
Genotype frequencies of SNP16 (rs324148) and SNP18 (rs9394992) in AML patients and healthy control, and their impact on the mRNA expression of SLC29A1. a, genotype frequencies of SNP16 (rs324148) in remission and relapsed patients, and in healthy control. Frequency of genotype CC was higher in relapsed patients than those of CT and TT (P = 0.04); b, genotype frequencies of SNP18 (rs9394992) in remission and relapsed patients, and in healthy control. Frequencies of genotype CT and TT were higher in relapsed patients than those of CC (P = 0.0004). No difference of genotype frequencies of both SNPs was observed between healthy control and remission patients. c, relative mRNA expression of SLC29A1 in patients with different genotypes of SNP16 and SNP18 by quantitative real time PCR, β-actin was used as an internal control. *# + $^ indicated statistically significant (P < 0.05).
Figure 5
Figure 5
Univariate analysis of survival rates based on genotypes of SNP16 (rs324148) and SNP19 (rs9394992). a: effect of SNP16 on OS of AML, b: effect of SNP16 on DFS of AML; c, effect of SNP18 on OS of AML; d, effect of SNP18 on DFS of AML.
Figure 6
Figure 6
Effect of SNP-SNP interactions on OS and DFS of patients with AML. a, combined effects of SNP16 and SNP18 on OS of patients with AML; b, combined effects of SNP16 and SNP18 on DFS of patients with AML.
Figure 7
Figure 7
Univariate analysis of cytogenetic abnormalities on DFS and OS of patients with AML. Effect of cytogenetic abnormalities on OS and DFS. a, Effects of cytogenetic abnormalities on DFS; b, Effects of cytogenetic abnormalities on OS. Risk status was evaluated according to the NCCN guidelines version 2.2014 for AML (https://www.nccn.org).
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