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Aim: To clarify the association between genetic factors related to angiogenesis and feeling of incomplete bladder emptying among older community-dwelling individuals., Method: A cross-sectional study of 1762 (607 men and 1155 women) older Japanese individuals aged 60-79 years with data on rs3025020 was conducted, because vascular endothelial growth factor (VEGF), which contributes to the progression of angiogenesis, has been reported to be positively associated with the minor allele (T) of polymorphism rs3025020., Results: In the study population, 155 (103 men and 52 women) had feeling of incomplete bladder emptying. With rs3025020 (C/C) as the reference group, rs3025020 (T/T) was associated with a significantly higher odds ratio (OR) for feeling of incomplete bladder emptying. The adjusted ORs and 95% confidence intervals were 3.01(1.53, 5.93) in men and 2.48 (1.09, 5.66) in women, respectively., Conclusion: VEGF polymorphism rs3025020 was associated with feeling of incomplete bladder emptying among older community-dwelling individuals. Development of angiogenesis could be associated with feeling of incomplete bladder emptying in older individuals. Geriatr Gerontol Int 2024; 24: 1039-1044., (© 2024 Japan Geriatrics Society.)

Purpose: Treatment with regorafenib, which inhibits vascular endothelial growth factor (VEGF) receptor, frequently results in hand-foot skin reaction (HFSR), requiring treatment discontinuation or dose reduction. In our prospective study of regorafenib on patients with metastatic colorectal cancer, 17% of patients developed grade 3 HFSR. Herein, we retrospectively examined genetic polymorphisms associated with regorafenib-induced severe HFSR., Methods: To identify associated polymorphisms, exploratory whole-exome sequencing focusing on factors related to VEGF-mediated signaling pathways was first performed in seven patients each, with grade 3 HFSR and without HFSR. The identified HFSR-associated polymorphisms were analyzed in all the 40 patients., Results: The genotype frequency of rs3025009 G/A or A/A in the gene encoding VEGF-A (VEGFA) in patients with ≥ grade 2 HFSR was significantly higher than in other patients (P = 0.0257, Pc = 0.0771 [Bonferroni correction]). The frequency of C-C motif of chemokine ligand 4-like 2 (CCL4L2) rs3744596 A/T or T/T in patients with grade 3 HFSR was significantly lower than in others (P = 0.00894, Pc = 0.0268). The combination of the risk genotypes VEGFA rs3025009 G/A or A/A and CCL4L2 rs3744596 A/A was significantly associated with a higher incidence of grade 3 (P = 0.000614, Pc = 0.00246) and a longer median progression-free survival (P = 0.0234) than others., Conclusions: These VEGF-related polymorphisms were found to be associated with HFSR and the survival benefits of regorafenib treatment., Trial Registration Number and Date: UMIN000013939, registered on May 12, 2014, when 6 months after the approval by the Institutional Review Board of Showa University., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Driver mutations at BRAF V600 are frequently identified in papillary thyroid cancer and anaplastic thyroid cancer (ATC), in which BRAF inhibitors have shown clinical effectiveness. This Japanese phase 2 study evaluated the efficacy and safety of a BRAF inhibitor, encorafenib, combined with an MEK inhibitor, binimetinib, in patients with BRAF V600-mutated thyroid cancer. Methods: This phase 2, open-label, uncontrolled study was conducted at 10 institutions targeted patients with BRAF V600-mutated locally advanced or distant metastatic thyroid cancer not amenable to curative treatment who became refractory/intolerant to ≥1 previous vascular endothelial growth factor receptor-targeted regimen(s) or were considered ineligible for those. The primary endpoint was centrally assessed objective response rate (ORR). The secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: We enrolled 22 patients with BRAF V600E -mutated thyroid cancer: 17 had differentiated thyroid cancer (DTC), and 5 had ATC. At data cutoff (October 26, 2022), the median follow-up was 11.5 (range = 3.4-19.0) months. The primary endpoint of centrally assessed ORR was 54.5% (95% confidence interval [CI] 32.2-75.6; partial response in 12 patients and stable disease in 10). The ORRs in patients with DTC and ATC were 47.1% (8 of 17) and 80.0% (4 of 5), respectively. The medians for DOR and PFS by central assessment and for OS were not reached in the overall population, the DTC subgroup, or the ATC subgroup. At 12 months, the rate of ongoing response was 90.9%, and the PFS and OS rates were 78.8% and 81.8%, respectively. All patients developed ≥1 adverse events (AEs): grade 3 AEs in 6 patients (27.3%). No patients developed grade 4-5 AEs. The most common grade 3 AE was lipase increased (4 patients [18.2%]). Those toxicities were mostly manageable with appropriate monitoring and dose adjustment. Conclusions: Treatment with encorafenib plus binimetinib met the primary endpoint criteria and demonstrated clinical benefit in patients with BRAF V600E Japan Registry of Clinical Trials: jRCT2011200018.BRAF V600-mutated thyroid cancer. Clinical Trial Registration number: Japan Registry of Clinical Trials: jRCT2011200018.

A deteriorated liver functional reserve during systemic therapy for unresectable hepatocellular carcinoma (HCC) causes poor patient outcomes. We aimed to identify predictive factors associated with the deterioration of Child-Pugh score at 8 weeks after lenvatinib initiation. Patients with adequate clinical data and baseline preserved serum samples available were included. Baseline fibroblast growth factor (FGF)19 and 21, angiopoietin (ANG)2, and vascular endothelial growth factor (VEGF) levels were evaluated. Thirty-seven patients were included, and 6, 15, 14, and 2 experienced complete response, partial response, stable disease, and progressive disease, respectively. Twenty-four (65%) and 13 (35%) patients showed a maintained/improved and deteriorated Child-Pugh-score, respectively. While baseline clinical data, treatment response, and laboratory data were similar between these two patient groups, baseline ANG2 and VEGF levels were significantly higher (P = 0.0017) and lower (P = 0.0231), respectively, in patients with deteriorated Child-Pugh score than in those without. Based on receiver operating characteristic curve analysis, cut-off values for ANG2 and VEGF were found to be 3,108 pg/mL and 514.9 pg/mL, respectively. Among patients with low VEGF and high ANG2, 89% (8/9) exhibited a deteriorated Child-Pugh score, whereas none of the patients (0/9) with high VEGF and low ANG2 did. The deterioration of the Child-Pugh score in patients with unresectable HCC who are treated with lenvatinib may be predictable based on combined baseline serum ANG2 and VEGF levels., Competing Interests: Professor Naoya Sakamoto has received lecture fees from Bristol Myers Squibb and Pharmaceutical K.K., grants and endowments from MSD, K.K., and Chugai Pharmaceutical Co., Ltd., and a research grant from Gilead Sciences Inc. and AbbVie GK. Dr. Goki Suda has received research grants from Merck & Co, Gilead Sciences Inc., and Bristol Myers Squibb. The other authors have no conflicts of interest to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Recently, short stature has been revealed to be positively associated with hypertension, possibly because this indicates lower activity of vascular maintenance, such as angiogenesis. Vascular endothelial growth factor (VEGF) polymorphism (rs3025020) plays an important role in the progression of angiogenesis and may be associated with both hypertension and hypertension-associated short stature., Methods: A cross-sectional study of 1377 elderly Japanese individuals aged 60-89 years was conducted. Short stature was defined as the lowest tertile of height (< 160.8 cm for men and < 148.7 cm for women). Hypertension was defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg and/or antihypertensive medication use., Results: Independent of known cardiovascular risk factors, short stature was found to be positively associated with hypertension; the fully adjusted odds ratio (OR) and 95% confidence interval (CI) for hypertension were 1.51 (1.17, 1.96). With the reference group of carriers of the major allele of rs3025020, TT-homozygotes showed significantly lower OR for hypertension and short stature; the fully adjusted ORs (and 95% CIs) were 0.60 (0.41, 0.90) for hypertension and 0.59 (0.38, 0.91) for short stature, respectively., Conclusions: Angiogenesis-related genetic factor (rs3025020) is associated with hypertension and short stature, whereas short stature is positively associated with hypertension. Further investigation is necessary in this regard; the capacity for angiogenesis might partly explain the mechanism underlying the inverse association between height and hypertension.

Objective: Ramucirumab is a recombinant human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. The aim of this phase 1 study was to evaluate the safety and tolerability of ramucirumab monotherapy in Japanese patients with advanced solid tumors., Methods: Patients with solid tumors who had not responded to standard therapy or for whom no standard therapy was available received escalating doses of ramucirumab, administered once every 2 (Q2W) or 3 (Q3W) weeks. The primary objective was to establish the safety and pharmacokinetic profiles of ramucirumab. Secondary and exploratory objectives included assessment of immunogenicity and antitumor activity. ClinicalTrials.gov: NCT01005355., Results: Fifteen patients were treated with ramucirumab at a dose of 6 mg/kg Q2W (N = 3), 8 mg/kg Q2W (N = 6) or 10 mg/kg Q3W (N = 6). There were no dose-limiting toxicities and the maximum tolerated dose was not reached. The most common ramucirumab-related adverse events were headache, pyrexia, hypertension and increased aspartate aminotransferase. Following single-dose administration of ramucirumab, there appeared to be a dose-proportional increase in maximum observed drug concentration but not in area under the curve. Treatment-emergent anti-ramucirumab antibodies were not detected in any patient., Conclusions: Ramucirumab monotherapy was well tolerated and feasible at the doses and schedules used in this study population of Japanese patients with advanced solid tumors., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Purpose: To correlate a genetic risk score based on age-related macular degeneration (AMD) susceptibility genes with the risk of AMD in the second eye., Methods: This is a retrospective, open cohort study consisting of 891 unilateral AMD patients, who were followed for at least 12 months and recruited from three institutes. DNAs were genotyped using Illumina OmniExpress, HumanOmni2.5-8, and/or HumanExome. Survival analyses and Cox proportional hazard models were used to examine the association between 11 AMD susceptibility genes and the duration until second-eye involvement in 499 samples from Kyoto University, which were replicated in two other cohorts. Genetic risk score (GRS) was also evaluated., Results: The ARMS2 rs10490924 recessive model (hazard ratio [HR]meta = 2.04; Pmeta = 3.4 × 10⁻³) and CFH rs800292 additive model (HRmeta = 1.77; Pmeta = 0.013) revealed significant associations with second-eye involvement. The dominant model of TNFRSF10A rs13278062, VEGFA rs943080, and CFI rs4698775 showed consistent effects across three datasets (I² = 0%; HRmeta = 1.46, 1.30, 1.51, respectively). The GRS using these five single nucleotide polymorphisms (SNPs) was also significantly associated (HRmeta [per score] = 2.42; P = 2.2 × 10⁻⁵; I² = 0%). After 10 years from the first visit, the patients within the top 10% by GRS showed a 51% hazard rate, in contrast to 2.3% among patients within the lowest 10% by GRS., Conclusions: We demonstrated that the GRS using ARMS2, CFH, TNFRSF10A, VEGFA, and CFI was significantly associated with second-eye involvement. Genetic risk has high predictive ability for second-eye involvement of AMD.

Background: Reports have been accumulating that genetic properties are predictive of clinical response after and/or toxicity during cancer chemotherapy, but little information is available concerning effects on long-term survival. In this study, 49 Japanese patients with esophageal squamous cell carcinoma (ESCC) were followed up for 5 years after treatment with a definitive 5-fluorouracil (5-FU)/cisplatin (CDDP)-based chemoradiotherapy (CRT), and the effects of genotypes of vascular endothelial growth factor (VEGF) were retrospectively revaluated in terms of prediction of long-term survival., Methods: A course consisted of the continuous infusion of 5-FU at 400 mg/m(2)/day for days 1-5 and 8-12, the infusion of CDDP at 40 mg/m(2)/day on days 1 and 8, and radiation at 2 Gy/day on days 1 to 5, 8 to 12, and 15 to 19, with a second course repeated after a 2-week interval. The VEGF genotypes -1498T/C, -1154G/A, -634C/G, -7C/T, 936C/T, and 1612G/A were evaluated., Results: The complete response (CR) rate was 46.9% (23/49). The 5-year survival rate was 42.9 % (21/49). There were 7 patients with a CR, but survival of less than 5 years. They died from myocardial infarction (N=1), sudden cardiac death after suffering from heart failure (N=1), acute myeloid leukemia that developed from myelodysplastic syndromes (N=1), factors not specified (N=2), oropharynx cancer (N=1), and tongue cancer (N=1). VEGF -634C/G had no effect on clinical response, but long-term survival depended on the genotype (p=0.033, Fisher's; p=0.038, Cochran-Armitage; p=0.079, Log-rank). The genotype frequency of 7 patients with a CR, but survival of less than 5 years was different from that for the other 42 patients (p=0.032, Fisher's). None of the other 5 genotypes evaluated affected either clinical response or survival., Conclusions: VEGF -634C/G is possibly predictive of long-term survival after treatment with a definitive 5-FU/CDDP-based CRT. Further clinical studies with a larger number of cases are needed to clarify the effects of this genotype.

Purpose: To describe phenotype and genotype characteristics of age-related macular degeneration (AMD) in Japanese patients., Design: A case-control study., Participants: A total of 550 case-control samples composed of 408 consecutive AMD cases and 142 controls., Methods: Clinical information assessing age, gender, affected eyes, fundus features, and fluorescein/indocyanine green angiograms were systematically evaluated. Four single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996, rs2274700) in the complement factor H (CFH) gene, 1 SNP (rs11200638) in the high-temperature requirement factor A1 (HTRA1) gene, 3 SNPs (rs699947, rs1570360, rs2010963) in the vascular endothelial growth factor (VEGF) gene, and 4 SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the pigment epithelium-derived factor (PEDF) gene were assessed using TaqMan technology., Main Outcome Measures: The clinical phenotype information and genotypes of CFH, HTRA1, VEGF, and PEDF polymorphisms., Results: Of Japanese patients with neovascular AMD (nAMD), 219 (58.7%) had typical nAMD and 154 (41.3%) had polypoidal choroidal vasculopathy (PCV). The frequency of bilateral exudative involvement was similar between typical nAMD (15.5%) and PCV (13.6%) (P = 0.613). Significant soft drusen were observed in the fellow eyes of 88 (47.6%) of 185 patients with unilateral typical nAMD and in 25 (18.8%) of 133 patients with unilateral PCV (P = 1.24x10(-7)). A serous pigment epithelium detachment was seen in 55 (25.1%) of 219 patients with typical nAMD and in 64 (41.6%) of 154 patients with PCV. A significant association was noted in CFH-rs800292, CFH-rs1410996, CFH-rs2274700, and HTRA1-rs11200638 with AMD development (P = 2.36x10(-5), 7.18x10(-5), 7.18x10(-5), 2.70x10(-7), respectively; population attributable risk = 57.3%, 57.8%, 57.8%, and 58.9%, respectively). We estimated the highest-risk group to have an approximately 70-fold greater risk of nAMD compared with the lowest-risk group when analyzing a combination of 4 SNPs in the CFH and HTRA1 genes., Conclusions: The Japanese AMD phenotype is characterized by a higher frequency of PCV, male predominance, and lower frequency of bilateral presentation compared with Caucasian AMD. Genotype analyses demonstrate a significant population attributable risk for SNPs in the CFH and HTRA1 genes and demonstrate joint effects for both genes. Gene variants in both CFH and HTRA1 contribute significantly to the AMD phenotype in a Japanese population., (Copyright 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Contagious dermatitis in domestic and wild ruminants caused by parapoxvirus (PPV) occurs worldwide. Although PPV infections appear in cattle, sheep and goats, the papular, nodular, pustular and ulcerated skin lesions of wild Japanese serows (Capricornis crispus) are significantly more severe than those of other animals. To determine the factors involved in the severity of these skin lesions, we compared the molecular characteristics of 4 PPV isolates from Japanese serows and 2 isolates from sheep in Japan, and also investigated the biological properties of primary endothelial cells from different host species. All of the 6 Japanese isolates harbored a vascular endothelial growth factor (VEGF) gene, which is known as one of the virulence factors of PPVs. Three different amino acid sequences of viral VEGF were identified and the sequence was identical among the 4 isolates from the Japanese serows. The temporal expression pattern of viral VEGF mRNA was almost the same among 3 isolates encoding the 3 different VEGFs in infected cells from different host species. Recombinant forms of the 3 different VEGFs showed the ability to induce vascular permeability and endothelial cell proliferation. Primary endothelial cells from Japanese serows were most responsive to recombinant viral VEGF compared to cells from cattle, sheep, and goats. These results suggest that not only the biological activity of viral VEGF but also the high responsiveness to viral VEGF of endothelial cells might be involved in the severe proliferative skin lesions induced by PPV infection in Japanese serows.

A complex interaction of host genetic and environmental factors may be relevant in the development of Helicocobacter pylori-related gastric carcinogenesis. We investigated the effect of vascular endothelial growth factor (VEGF) gene polymorphisms on the risk of gastric cancer (GC) and peptic ulcer diseases in a Japanese population. The G1612A(rs10434) and C936T(rs3025039) polymorphisms in the 3' untranslated region (3'-UTR) of VEGF gene were genotyped in a total of 844 subjects including 385 GC, 143 ulcer including 98 gastric ulcer (GU), 45 duodenal ulcer (DU), and 316 nonulcer subjects. The 1612A carrier held a significantly higher risk of GC when compared to both noncancer and nonulcer (overall noncancer vs. GC; OR = 1.61, 95% CI = 1.17-2.21, P = 0.0038, nonulcer vs. GC; OR = 1.54, 95% CI = 1.07-2.22, P = 0.0197). The 1612A carrier was more closely associated with an increased risk of noncardiac cancer (OR = 1.64, 95% CI = 0.17-2.21, P = 0.0038), lower third cancer (OR = 1.97, 95% CI = 1.30-3.00, P = 0.002), and Lauren's diffuse-type cancer (OR = 1.75, 95% CI = 1.24-2.46, P = 0.001), while the same genotype was not associated with the progression of GC. The C936T genotype was not associated with a risk of GC and its progression. Both the G1612A and C936T genotypes were not associated with the risk of peptic ulcer diseases. Our data suggest that the G1612A, but not C936T polymorphisms in the 3'-UTR of VEGF gene is associated with the susceptibility to GC in the Japanese population.

Background and Objective: Based on the reported biological properties and function of vascular endothelial growth factor (VEGF) in hypoxic conditions, many investigations have studied the hypothesis that VEGF has an important role in the pathogenesis of high altitude sicknesses, including high-altitude pulmonary oedema (HAPE). Unfortunately, the results are inconsistent. Therefore, the association of VEGF gene single nucleotide polymorphisms (SNP) with being susceptible to HAPE was investigated., Methods: The study included 53 HAPE-susceptible subjects (HAPE-s) and 69 HAPE-resistant mountaineer controls (HAPE-r). Subjects were Japanese and the two groups were comparable in terms of age and gender. The SNP of the VEGF gene, namely C-2578A, G-1154A and T-460C in the promoter, G + 405C in the 5'-untranslated region and C936T in the 3'-untranslated region, were examined by allele discrimination experiments. In addition, arterial oxygen tension (PaO(2)) and pulmonary haemodynamic data were available for 21 of the HAPE-s subjects., Results: There were no statistically significant differences in the allele frequencies, genotype distributions or haplotype frequencies of VEGF SNP between the HAPE-s and HAPE-r groups. Furthermore, neither PaO(2) nor pulmonary haemodynamic parameters were associated with the VEGF SNP in the 21 HAPE-s subjects., Conclusions: This genetic study did not provide evidence that functional SNP of the VEGF gene are associated with susceptibility to HAPE in a Japanese population.

Background: The development of diabetic retinopathy is associated with the duration of diabetes and HbA1c levels. However, the familial aggregation of diabetic retinopathy is consistent with genetic susceptibility. Recently, a -634C/G polymorphism in the vascular endothelial growth factor (VEGF) gene was shown to be associated with diabetic retinopathy. To clarify the contribution of the VEGF gene in the development of diabetic retinopathy we analyzed variants in this gene among 469 Japanese patients with type 2 diabetes., Methods: DNA from each patient was typed for -634C/G and -2578C/A polymorphisms using conventional polymerase chain reaction techniques. The vitreous fluid samples were obtained from 40 patients with PDR for measurement of VEGF levels., Results: We found a significantly higher frequency of the A allele in the group with proliferative diabetic retinopathy (PDR) than in the control group at -2578C/A polymorphism (p = 0.036). Moreover, if the subjects were grouped according to the duration of diabetes and status of diabetic retinopathy (a first group consisting of subjects with longer duration (>20 y) of diabetes without any retinopathy (n = 102), and a second group of those with shorter diabetes (<15 y) but having retinopathy (n = 35), the genotype distribution at -2578 C/A polymorphism was again significantly higher in the second group (p = 0.005) and differed significantly (p = 0.002) in a recessive model. The risk of the AA for PDR was 7.7 (95%, CI: 1.8-30.9)., Conclusions: The AA genotype at -2578C/A polymorphism in the VEGF gene is associated with proliferative diabetic retinopathy. No significant association with -634 C/G polymorphism was confirmed.

This study was conducted to evaluate the association between systemic exposure to 5-fluorouracil (5-FU) and genetic polymorphisms of vascular endothelial growth factor (VEGF) with clinical outcomes to a 5-FU/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma (ESCC). Forty-nine patients with ESCC (I/II/III/IVa = 11/9/17/7, with 5 postoperative recurrences) were enrolled into this study. One course of treatment consisted of protracted venous infusions of 5-FU (400 mg/m2/24 hr for day 1-5 and 8-12) and cisplatin (40 mg/m2/3 hr on day 1 and 8), and radiation (2 Gy/day on day 1-5, 8-12, and 15-19); a second course was repeated after a 2 week interval. A total of eight measurements of the plasma concentration of 5-FU were made per patient to evaluate its systemic exposure as area under the concentration time curve for 480 hours (AUC480h), and VEGF genotypes of T-1498C, G-1154A, C-634G, C-7T, C936T, and G1612A were evaluated. The mean value of AUC480h in the patients with a complete response was 58.7 +/- 16.8 mg*h/L, which was higher than that in the others, 49.0 +/- 10.9 mg*h/L (P = 0.029), whereas no such association was found for severe acute toxicities. VEGF genotype was not associated with the clinical response, whereas VEGF G-1154A resulted in severe acute leukopenia (P = 0.042) and severe acute cheilitis (P = 0.025). In conclusion, VEGF G-1154A was a predictor of severe acute toxicities during 5-FU/cisplatin-based chemoradiotherapy in Japanese ESCC patients, whereas the AUC480h value of 5-FU was predictive of the clinical response.

Background: Previously, MDR1 T-129C polymorphism, encoding multidrug resistant transporter MDR1/P-glycoprotein, was reported to be predictive of poorly-differentiated colorectal adenocarcinomas. Here, VEGF T-1498C, C-634G and C-7T polymorphisms, encoding vascular endothelial growth factor (VEGF), were investigated in terms of their association with differentiation grade., Methods: VEGF genotypes were determined by TaqMan(R) MGB probe based polymerase chain reaction and evaluated were confirmed by direct sequencing in 36 Japanese patients., Results: VEGF T-1498C, but not C-634G or C-7T, was predictive of poorly-differentiated ones, and thereby a poor prognosis (p = 0.064 for genotype, p = 0.037 for allele), and this effect can be explained by that on VEGF expression. Treatment of a colorectal adenocarcinoma cell line, HCT-15, with sodium butyrate, a typical differentiating agent, resulted in an increase of alkaline phosphatase activity and MDR1 mRNA expression, but in a decrease of VEGF mRNA expression. The transfection of VEGF small interfering RNA (siRNA) induced the expression of MDR1 mRNA to 288-332% of the control level, whereas MDR1 siRNA had no effect on VEGF mRNA expression., Conclusions: VEGF T-1498C polymorphism is also a candidate marker predictive of poorly-differentiated colorectal adenocarcinomas, but further investigations with a large number of patients should be addressed to draw a conclusion.

The mRNA expression of vascular endothelial growth factor (VEGF) was evaluated in colorectal adenocarcinomas and adjacent noncancerous colorectal tissues in 18 Japanese patients. The expression was confirmed to be up-regulated in the colorectal adenocarcinomas, when compared with the noncancerous tissues. Twelve genotypes of VEGF: six positions in the promoter region, two in the 5'UTR, and four in the 3'UTR, and their association with the expression of VEGF mRNA were evaluated. While G-1877A, T-1455C, G-1154A, C702T, and G1612A were not detected, C-2578A, T-1498C, G-1190A, C-634G, C-7T, C936T, and C1451T were found at allele frequencies of 4/36, 15/36, 15/36, 20/36, 8/36, 6/36, and 6/36, respectively, suggesting that C-2578A, G-1154A, and G1612A were associated with a decreased risk for colorectal adenocarcinoma. T-1498C (G-1190A) and C-7T were found to be associated with higher levels of VEGF mRNA, and may be a risk factor for the development of liver metastasis and/or prognosis of colorectal adenocarcinoma.