Associations Of VEGF and VEGFR2 Polymorphisms With Increased Risk and Aggressiveness Of Multiple Myeloma

Increased angiogenesis (AG) has been demonstrated in the bone marrow microenvironment in multiple myeloma (MM), suggesting its potential pathophysiologic role in the disease. The most important mediators of AG during tumor development are the vascular endothelial growth factor (VEGF) and the vascular endothelial growth factor receptor 2 (VEGFR2). Both factors are encoded by polymorphic genes and, therefore, their levels or functions are variable in healthy humans. It is already known that allele C of the VEGF 2578C/A (rs699947), allele G of the 1154G/A (rs1570360) and allele C of the 634 G/C (rs2010963) are related to higher concentration of serum VEGF compared to the remaining alleles. It is also established that the G allele of the VEGFR2 1192G/A (rs2305948) has higher binding efficiency and the allele C of the VEGFR2 604T/C (rs2071559) has lower transcription activity. Since the roles of these genetic polymorphisms in the risk and clinical manifestation of MM are still unknown, these were the aims of the present study.

Genomic DNA from peripheral blood of 192 consecutive MM patients and 202 age and race-matched controls was analyzed by real-time polymerase chain reaction for genotyping of the above mentioned polymorphisms. The differences between groups were analyzed by the logistic regression model. Power analysis (PA) was used to verify the effect of sample size on the results obtained in the study.

The VEGF 2578CC genotype alone or combined with VEGF 634GG and VEGFR2 1192GG was higher in patients than in controls (47.4% versus 36.8%, P=0.01, PA: 88%; 44.3% versus 20.0%, P=0.001, PA: 99%; 71.3% versus 58.9%, P=0.01, PA: 81%; respectively). Carriers of these genotypes had a 1.89, 5.52 and 2.56 increased risks for MM than those with the remaining genotypes, respectively. Also, the VEGF 634GG genotype combined with VEGF 2578CC and VEGF 1154GG genotypes, with VEGF 2578CC and VEGFR2 1192GG genotypes and with VEGF 1154GG and VEGFR2 604TT genotypes were higher in patients than in controls (43.3% versus 32.5%, P=0.006, PA: 96%; 66.7% versus 32.0%, P=0.004, PA: 96%; 30.5% versus 12.5%, P=0.001, PA: 99%, respectively). Carriers of these genotypes had a 4.91, 10.97 and 14.10 increased risks for MM than those with the remaining genotypes, respectively. When only patients were analyzed, SNPs on the AG pathway were associated with clinical features. The VEGFR2 1192GG genotype, alone or combined with VEGF 2578CC and VEGF 1154GG, was related with lower counts of plasma cells in the bone marrow (80.4% versus 64.4%, P=0.03; PA: 52.5%; 80.5% versus 60.0%, P=0.02, PA: 44.4%; 85.1% versus 67.8%, P=0.01; PA: 42.8%, respectively). The frequency of the VEGFR2 604TT genotype was higher in patients with tumors of II and III Durie & Salmon stages than in those with tumors of stage I (29.9% versus 9.1%, P=0.02; PA: 75.5%). The VEGF 634GG genotype, alone or combined with VEGFR2 1192GG, was related to lower rates of renal failure (53.2% versus 35.3%, P=0.02; PA: 59.3%; 76.7% versus 53.8%; P=0.02, PA: 59.1%, respectively).

The data present, for the first time, preliminary evidence that inherited abnormalities of AG pathways, specifically SNPs on VEGF and VEGFR2, alone or combined, alter the risk for MM and clinical features of the disease.

No relevant conflicts of interest to declare.