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

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

Carol Lozano-Santos  1 , Jimena Martinez-Velasquez  2 , Belen Fernandez-Cuevas  1 , Natividad Polo  1 , Belen Navarro  1 , Isabel Millan  3 , Jose Miguel Garcia  4 , Rosa Collado  5 , Pedro Sanchez-Godoy  6 , Felix Carbonell  5 , Jose Antonio Garcia-Vela  7 , Jose Antonio Garcia-Marco  1 , Natalia Gomez-Lozano  2
Affiliations

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

Carol Lozano-Santos et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: CLS received funding from Roche Farma for this work and has no other relationships, conditions or circumstances that present potential competing interests related with this work. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials. The rest of the authors declare no competing interests related with this work.

Figures

Figure 1
Figure 1. Association of VEGFA genotypes and OS of 239 CLL patients.
Kaplan-Maier curves according to: (A) a recessive comparison of rs699947/rs833061/rs2010963 ACG+/+ genotype and, (B) number of copies of ACG haplotype.
Figure 2
Figure 2. Association of VEGFA ACG+/+ genotype and OS of CLL patients with good prognostic features.
Kaplan-Maier curves according to VEGFA ACG+/+ genotype (solid line) and other genotypes (dotted line) in subgroups of patients divided by (A) age at diagnosis, (B) IgVH mutational status, (C) Binet stage, (D) CD38 status and, (E) genetic abnormalities. aVery low (del13q), low (normal karyotype), intermediate (ΔATM) and high-risk (ΔTP53).
See this image and copyright information in PMC

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