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

Wan H, Zhu J, Chen F, Xiao F, Huang H, Han X, Zhong L, Zhong H, Xu L, Ni B, Zhong J - J. Exp. Clin. Cancer Res. (2014)

Bottom Line: This study aimed to assess the pharmacogenomic effects of Ara-C metabolic pathway in patients with AML.The association between clinical outcome and gene variants was evaluated by Kaplan-Meier method.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]).

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China. aurorawan@126.com.

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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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.
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Fig3: 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.

Mentions: 19 SNPs (Table 2) of DCK, CDA and SLC29A1 were screened in 100 AML patients and 100 healthy controls, and their genotype frequencies and allele frequencies were summarized (Additional file 2). SNP15 was excluded from analysis since only one genotype was identified in the AML patients and normal healthy controls. Genotype frequencies of the other 18 SNPs were identified in Hardy-Weinberg equilibrium (χ2 = 0.002-3.590, P = 0.580-0.960). No difference of genotype and allele frequencies of all the 18 SNPs were found between the AML patients and the healthy controls. Genotype frequencies were not significantly different between male and female AML patients. No significant correlation was observed between other AML prognostic factors including WBC at presentation, age or cytogenetic abnormalities, and genotypes of SLC29A1 polymorphic variants. The two SNPs of SLC29A1b, rs324148 and rs9394992, were not in strong linkage disequilibrium (LD) (D’ = 0.73, r2 = 0.11) in CHB as well as LD and CEU (D’ = 0.38, r2 = 0.03) (Figure 3a, b).Table 2


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

Wan H, Zhu J, Chen F, Xiao F, Huang H, Han X, Zhong L, Zhong H, Xu L, Ni B, Zhong J - J. Exp. Clin. Cancer Res. (2014)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4234887&req=5

Fig3: 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.
Mentions: 19 SNPs (Table 2) of DCK, CDA and SLC29A1 were screened in 100 AML patients and 100 healthy controls, and their genotype frequencies and allele frequencies were summarized (Additional file 2). SNP15 was excluded from analysis since only one genotype was identified in the AML patients and normal healthy controls. Genotype frequencies of the other 18 SNPs were identified in Hardy-Weinberg equilibrium (χ2 = 0.002-3.590, P = 0.580-0.960). No difference of genotype and allele frequencies of all the 18 SNPs were found between the AML patients and the healthy controls. Genotype frequencies were not significantly different between male and female AML patients. No significant correlation was observed between other AML prognostic factors including WBC at presentation, age or cytogenetic abnormalities, and genotypes of SLC29A1 polymorphic variants. The two SNPs of SLC29A1b, rs324148 and rs9394992, were not in strong linkage disequilibrium (LD) (D’ = 0.73, r2 = 0.11) in CHB as well as LD and CEU (D’ = 0.38, r2 = 0.03) (Figure 3a, b).Table 2

Bottom Line: This study aimed to assess the pharmacogenomic effects of Ara-C metabolic pathway in patients with AML.The association between clinical outcome and gene variants was evaluated by Kaplan-Meier method.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]).

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China. aurorawan@126.com.

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.

Show MeSH
Related in: MedlinePlus