Vascular Endothelial Growth Factor A (VEGFA) Gene Polymorphisms Have an Impact on Survival in a Subgroup of Indolent Patients with Chronic Lymphocytic Leukemia

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.

Association of VEGFA-2578 C>A polymorphism with clinicopathological aspects and outcome in follicular lymphoma patients

“… 11 , 12 In contrast, a VEGFA haplotype, including the rs699947 locus, had deleterious effects in CLL patients. 13 Our results and those found in CLL support that AG modulation by rs699947 may be relevant driving indolent lymphoproliferative diseases to unfavorable outcomes.…”

“…The SNP did not influence the survival of MCL 11 and diffuse large B-cell lymphoma (DLBCL) patients, 12 but a VEGFA haplotype, including the rs699947 locus, determined worse prognosis in chronic lymphocytic leukemia (CLL) patients. 13 To the best of our knowledge, the roles of VEGFA -2578 C>A SNP in FL susceptibility, clinicopathological features and outcome are still unknown, and, therefore, these were the aims of this study. Moreover, we investigated a possible functional role of rs699947 in FL, by combining genotyping with the analysis of AG and LG markers in the patients' biopsies.…”

Angiogenic factors in chronic lymphocytic leukaemia (CLL): Where do we stand?

“…In fact, recent research exploring the mechanism of action of bevacizumab on CLL cells showed the efficiency of this monoclonal antibody in inducing apoptosis of leukaemia cells [13]. Whilst many studies highlight the importance of VEGF as target of research in CLL angiogenesis [7,11,[13][14][15][16][17], we are still refining our understanding of the VEGF family in the CLL context.…”

“…It is not only the overexpression of ligands and receptors that contributes to CLL severity. Recent research reveals that VEGF gene polymorphisms diversity modulates pathophysiology of CLL cells and that this diversity has an impact on overall survival in indolent CLL cases [16]. Since we are still unable to target VEGF in CLL patients, the recent evidence emphasised the impact of VEGF in the CLL microenvironment by controlling the expression of relevant VEGF receptors not only on CLL, but also on accessory Tregs and PDCs.…”

Effect of vascular endothelial growth factor-C expression on lymph node metastasis in human cholangiocarcinoma

“…Lymphatic metastasis plays a significant role in the process of cholangiocarcinoma metastasis, and the hepatic portal lymph node is the most commonly affected node. Tumor metastasis is a complex and multi-stage process in which a number of cytokines are now known to be involved, particularly the vascular endothelial growth factor (VEGF) family (3)(4)(5).…”