VEGFA and VEGFR2 Genetic Polymorphisms and Survival In Patients with Diffuse Large B Cell Lymphoma

Angiogenesis and angiogenic factors are increased in most lymphomas and it has been associated with adverse outcome or more aggressive behavior of malignant lymphomas in previous studies. There is substantial inherited genetic variability within VEGF and one of its receptors, VEGF receptor 2 (VEGFR2), including multiple single nucleotide polymorphisms (SNPs). The level of VEGF expression has been found to vary depending on the presence of a genetic polymorphism. Moreover, VEGFR2 gene polymorphisms affect the binding efficacy of VEGF to VEGFR2. We therefore assessed the association between VEGFA and VEGFR2 polymorphisms and survival outcomes in patients with diffuse large B cell lymphoma (DLBCL).

This study included 494 patients with de novo DLBCL treated at 5 hospitals throughout Korea from August 2001 through August 2009. Patients were included if they were (1) ethnic Koreans; (2) had blood samples taken at diagnosis; (3) had been treated with R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, prednisolone) with curative intent; and (4) were available for follow-up at the treating institution. Genes and polymorphisms known to modulate angiogenesis were selected. Criteria included: (1) SNPs involved in the VEGF pathway; (2) potentially functional SNPs predicting alterations in protein function; (3) SNPs relevant to outcomes in other settings; (4) and SNPs with a minor allele frequency >5% in the study population. We selected a total of five genotypes, three in the VEGFA gene (rs699947, rs833061, and rs3025039) and two in the VEGFR2 gene (rs1870377 and rs2305948).

There was a trend towards greater proportions of patients > 60 years (P=0.078) patients with bulky disease (P=0.072) and patients who did not achieved complete response (P=0.068) among the VEGF2R rs1870377 TT type than the TA+AA genotype patients.

Of the five polymorphisms, VEGF2R rs1870377T>A was significantly associated with both OS and PFS; in the dominant model, the TT genotype had worse OS (P=0.002) and PFS (P=0.004) than the AA+TA genotype. Among patients with low IPI scores (0 to 2), those with the VEGFR2 rs1870377 AA+TA genotype had significantly better OS (P=0.035); a similar difference for this genotype was observed among patients with high IPI scores (3 to 5) (P=0.043). Patients in the moderate (P=0.031) and high (P=0.043) risk subgroups, according to revised IPI scores, with the VEGFR2 rs1870377 AA+TA genotype also had better outcomes than those with the TT genotype.

Multivariate analysis showed that the rs1870377 genotype was an independent prognostic factor for OS (HR for TT vs AA+AT, 1.71; 95% CI, 1.21 to 2.43; P=0.002) and PFS (HR for TT vs AA+AT, 1.57; 1.13 to 2.17; P=0.007). Age > 60 years (P=0.0001 for OS; P=0.0001 for PFS), LDH level > normal (P=0.005 for OS; P=0.003 for PFS), extranodal disease > 1 (P=0.013 for OS; P=0.017 for PFS) and presence of B symptom (P=0.0001 for OS; P=0.0001 for PFS) were also independent prognostic factors for the survival of patients with DLBCL.

The VEGFR2 rs1870377 polymorphism may affect survival in patients with DLBCL. These findings suggest that increased angiogenic activity may be related to tumor progression in patients with DLBCL.

No relevant conflicts of interest to declare.