Clinical Relevance of Vascular Endothelial Growth Factor (VEGFA) and VEGF Receptor (VEGFR2) Gene Single Nucleotide Polymorphism on the Treatment Outcomes Following Imatinib Mesylate Therapy.

Abstract

Imatinib mesylate (IM) could reverse marrow angiogenesis and decrease the plasma level of vascular endothelial growth factor (VEGF) in chronic myeloid leukemia (CML) patients. The current study investigated the impact of 4 VEGF (VEGFA) and 3 VEGF receptor (VEGFR2) gene polymorphisms on the outcomes of 228 CML patients following IM therapy (male:female 96:132; median age at start of IM, 55 years-old; chronic phase: accelerated phase: blastic crisis, 205/17/2). The DNAs from blood samples were genotyped using MALDI-TOF-based method. VEGFA genotypes such as -2578C>A (rs699947), -460T>C (rs833061), +405G>C (rs2010963) and +936 C>T (rs3025039) loci, and VEGFR2 genotypes including rs1531289, rs1870377 and rs2305948 were analyzed. In single marker analyses, strong correlations were noted between complete cytogenetic response (CCyR) and VEGFR2 genotypes (rs1531289 and rs1870377), treatment failure and VEGFR2 genotype (rs1870377), dose escalation and VEGFR2 genotype (rs1870377), complete molecular response (CMoR) and VEGFA genotype (rs3025039), progression to advanced disease stage and VEGFA genotypes (rs699947 and rs833061). Three haplotypes of VEGFR2 gene were generated as follows: GT (46.1%), AT (27.9%) and GA (25.7%). Haplotype analyses showed good correlations between VEGFR2 haplotype and CCyR, treatment failure, and dose escalation of IM. Multivariate analyses confirmed strong correlations of VEGFR2 polymorphisms (especially rs1531289, rs1870377 or VEGFR2 haplotype) with CCyR, treatment failure, dose escalation and of VEGFA genotype (rs699947) with progression to advanced disease stage. The VEGFR2 genotypes and haplotype correlate well with cytogenetic response, treatment failure and dose escalation of IM therapy in CML patients, while VEGFA genotype correlates with progression to advanced disease stage.