Single-nucleotide polymorphisms (SNPs) in the endothelial nitric oxide synthase (NOS3) and vascular endothelial growth factor (VEGF) and its relationship to sunitinib-induced hypertension

4611 Background: Hypertension is a common side-effect in patients treated with sunitinib and is likely associated with inhibition of the VEGF/VEGF receptor(R)-2 pathway. SNPs in VEGF-A, VEGFR-2, but also in NOS3and endothelin-1 (EDN1) have been mentioned as possible candidates associated with a higher risk on development of hypertension.METHODS: A retrospective multicenter study was performed in 255 patients with advanced renal cell cancer and gastrointestinal stromal tumor treated with sunitinib 50 mg/day in a 4 weeks on 2 weeks off or 37.5 mg/day continuous schedule. Office systolic (SBP) and diastolic blood pressure (DBP) were measured at baseline and on days 14 and 28 of the first treatment cycle. Hypertension was graded according to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE). Seven SNPs in genes encoding for VEGF-A (rs2010963, rs833061, rs3025039, rs699947), VEGFR-2 (rs1870377), EDN1 (rs5370) and NOS3 (rs2070744) were selected. SNPs were univariately tested against hypertension grades according to CTCAE.RESULTS: During the first treatment cycle, sunitinib induced a mean increase of 13 ± 23 mmHg and 10 ± 12 mmHg in SBP and DBP (t-test, P < 0.001), respectively. According to CTCAE, 36.5 % of patients developed hypertension. Among these patients, 10.6%, 12.9% and 12.9% had hypertension grade 1, 2, and 3, respectively. Development of grade 3 hypertension was associated with two copies of the C-allele in VEGF-A (rs833061; Chi-square, P = 0.048), two copies of the A-allele in VEGF-A(rs699947; P = 0.053) and a C-allele in NOS3 (rs2070744; P = 0.051).CONCLUSIONS: SNPs in genes of NOS3 and VEGF-A are associated with the development of severe hypertension in patients treated with sunitinib. In particular, the association between the NOS3 pathway and hypertension induced by an inhibitor of the VEGF/VEGFR-2 pathway is a new finding. Hence, SNPs in VEGF-A and NOS3 genes may identify patients predisposed to develop hypertension on sunitinib treatment.