Vascular endothelial growth factor gene polymorphisms associated with treatment outcomes in de novo acute myeloid leukemia Free

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Angiogenesis has been known to be associated with the development, growth and prognosis of hematologic malignancies including acute myeloid leukemia (AML). Vascular endothelial growth factor (VEGF) is a key mediator in the process of angiogenesis. The current study investigated the impact of VEGF gene single nucleotide polymorphisms (SNPs) on the treatment outcomes of acute myeloid leukemia (AML). Four VEGF gene SNPs were analyzed in 138 patients with de novo AML using PCR/RFLP assay for -2578 (rs699947), -460 (rs833061), +405G>C (rs2010963) and +936 C>T (rs3025039) loci.

In genotype analyses, no associations were found between 4 SNPs and disease characteristics at diagnosis (cytogenetics, white cell counts, or LDH) or response to chemotherapy. The survival analyses showed significant correlation of C/T genotype at +936 with favorable 2-years leukemia free survival (51.3 ± 10.4%) versus C/C genotype (33.6 ± 6.3%, p=0.025).

A strong linkage disequilibrium was noted among loci -2578, -460 and +405 (D’=0.94 between -2578 and -460, 0.87 between -2578 and +405, and 1.0 between -460 and +405), but not with +936 (D’=0.26). Accordingly, 4 haplotypes were generated from genotype of -2578, -460, and +405 using Haploview software as follows: CTC (40.2%), CTG (35.0%), ACG (22.0%), and ATC (1.2%). The leukemia free survival inversely correlated with CTG haplotype in a dose dependent manner: 793 days vs. 350 days vs. 254 days in 0/1/2 allele(s) of CTG haplotype (p=0.034). The event free survival also showed similar pattern: 435 days, 182 days vs 35 days in 0/1/2 allele(s) of CTG haplotype (p=0.046). The overall survival curve also showed similar pattern, but with marginal significance (p=0.059).

We performed additional survival analysis based on +936 genotype and CTG haplotype, which suggested synergistic effect of VEGF gene SNP on the treatment outcomes in AML: LFS (p=0.011), EFS (p=0.033), and OS (p=0.013)

In conclusion, the present results suggest that the VEGF +936 C>T genotype and CTG haplotype may be associated with the prognosis of AML patients in a synergistic manner.