Vascular endothelial growth factor A (VEGFA) gene polymorphisms have an impact on survival in a subgroup of indolent patients with chronic lymphocytic leukemia

PLoS One. 2014 Jun 27;9(6):e101063. doi: 10.1371/journal.pone.0101063. eCollection 2014.

Abstract

Vascular endothelial growth factor (VEGF)-mediated angiogenesis contributes to the pathogenesis of B-cell chronic lymphocytic leukaemia (CLL). We investigated the impact of VEGFA gene diversity on the clinical outcome of patients with this disease. A VEGFA haplotype conformed by positions rs699947 (-1540C>A), rs833061 (-460T>C) and rs2010963 (405C>G) and two additional single-nucleotide polymorphisms (SNPs), rs3025039 (936C>T) and rs25648 (1032C>T), were analysed in 239 patients at the time of their CLL diagnosis. Here, we showed that homozygosity for rs699947/rs833061/rs2010963 ACG haplotype (ACG+/+ genotype) correlated with a reduced survival in CLL patients (ACG+/+ vs other genotypes: HR = 2.3, p = 0.002; recessive model). In multivariate analysis, the ACG+/+ genotype was identified as a novel independent prognostic factor (HR = 2.1, p = 0.005). Moreover, ACG homozygosity subdivided patients with CLL with otherwise indolent parameters into prognostic subgroups with different outcomes. Specifically, patients carrying the ACG+/+ genotype with mutated IgVH, very low and low-risk cytogenetics, initial clinical stage, CD38 negative status or early age at diagnosis showed a shorter survival (ACG+/+ vs other genotypes: HR = 3.5, p = 0.035; HR = 3.4, p = 0.001; HR = 2.2, p = 0.035; HR = 3.4, p = 0.0001 and HR = 3.1, p = 0.009, respectively). In conclusion, VEGFA ACG+/+ genotype confers an adverse effect in overall survival in CLL patients with an indolent course of the disease. These observations support the biological and prognostic implications of VEGFA genetics in CLL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers, Tumor / genetics*
  • Case-Control Studies
  • Female
  • Haplotypes
  • Homozygote
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / diagnosis
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Survival Analysis
  • Vascular Endothelial Growth Factor A / genetics*

Substances

  • Biomarkers, Tumor
  • Vascular Endothelial Growth Factor A

Grants and funding

This work was supported by Fundación para la Investigación Biomédica and Fondo de Investigación Sanitaria (FIS CP09-182), Instituto de Salud Carlos III. The authors were funded by the following institutions: NGL by a grant from programa Miguel Servet, Fondo de Investigación Sanitaria, Instituto de Salud Carlos III; CLS by a research grant from Roche Pharma and JMV by Fundación para la Investigación Biomédica Puerta de Hierro. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.