The association of K-ras gene mutation and vascular endothelial growth factor gene expression in pancreatic carcinoma.
BACKGROUND
Previously, the authors reported the role of the vascular endothelial growth factor (VEGF) as an angiogenic factor in 40 patients with pancreatic carcinoma. In this study, they investigated the mechanism underlying the regulation of VEGF gene expression and evaluated VEGF expression and K-ras gene status in 48 patients with pancreatic carcinoma.


METHODS
The authors used quantitative reverse transcriptase-polymerase chain reaction analysis and direct sequencing techniques for a retrospective study of VEGF gene expression and K-ras gene status in tumor tissue samples from 48 patients with pancreatic carcinoma. Immunohistochemistry also was used to investigate VEGF protein expression.


RESULTS
Thirty-one tumors (64.6%) were evaluated with high VEGF expression, and 17 tumors (35.4%) were evaluated with low VEGF expression. Of the 48 primary pancreatic tumors studied, 33 tumors (68.8%) contained mutations of the K-ras gene. There was a significant correlation between VEGF expression and K-ras status. Twenty-five of 33 tumors (75.8%) with mutant K-ras genes showed high VEGF expression, whereas only 6 of 15 tumors with the wild type K-ras (40.0%) showed high VEGF expression (P = 0.038). The mean (+/- standard error) VEGF conservation rate for the 33 tumors with mutant K-ras was 1.839 +/- 1.241, and that for the 15 tumors with wild type K-ras was 1.057 +/- 0.983 (P = 0.037). Furthermore, the median survival for patients with mutant K-ras was shorter than for those with wild type K-ras (10.6 months vs. 27.6 months, respectively; P = 0.026), whereas the median survival for patients with high VEGF expression was shorter compared with that for patients with low VEGF expression (9.5 months vs. 26.4 months, respectively; P = 0.002). Cox regression model analysis indicated that only the VEGF status was a significant factor for prognosis (P = 0.024). Other variables, i.e., K-ras status, histopathologic tumor grade, tumor status, lymph node status, metastatic status, gender, and age at surgery, were not significant.


CONCLUSIONS
The results of this study suggest that K-ras oncogene mutation may be associated with VEGF expression and that patients with pancreatic carcinoma who have high VEGF expression are associated with a poor prognosis.
Ikeda
N
N
Department of Thoracic Surgery and Department V of Oncology, Kitano Hospital, Tazuke Kofukai Medical Research Institute, 13-3, Kamiyama-cho, Kita-ku, Osaka 530-8480, Japan.
Nakajima
Y
Y
Sho
M
M
Adachi
M
M
Huang
C L
CL
Iki
K
K
Kanehiro
H
H
Hisanaga
M
M
Nakano
H
H
Miyake
M
M
D014408:Biomarkers, Tumor / Q000235:genetics*; D016228:Endothelial Growth Factors / Q000032:analysis / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D011905:Genes, ras; D005819:Genetic Markers; D006801:Humans; D007150:Immunohistochemistry; D008222:Lymphokines / Q000032:analysis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013223:Statistics as Topic; D016019:Survival Analysis; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D014408:Biomarkers, Tumor; D016228:Endothelial Growth Factors; D005819:Genetic Markers; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors