Von Hippel-Lindau Gene Mutations and Vascular Endothelial Growth Factor Immunoexpression in Clear Cell Renal Cell Carcinoma

Abstract

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults representing about 3% of all newly diagnosed cancers in the United States. Clear cell RCC is the most common subtype (70-80%) of RCC. Clear cell RCC can be familial, but 95% of cases are sporadic resulting from the germline or acquired mutation of Von Hippel-Lindau (VHL) gene. VHL tumor suppressor gene functions as a down regulator of vascular endothelial growth factor (VEGF). Mutations of VHL gene result in overexpression of VEGF, neoangiogenesis and tumor metastasis. Nowadays, anti-VEGF targeted therapy is used for treating metastasis clear cell RCC. However, drug resistance occurs over time. VHL gene targeted therapy combined with anti-VEGF therapy should be considered and detection of VHL gene mutations status becomes essential in these cases. The present study was aimed to detect the VHL gene mutations status and VEGF immunoexpression in 62 clear cell RCC patients by conventional polymerase chain reaction and immunohistochemistry. Three primer pairs were used to detect the mutations of 3 exons in VHL gene. The positive cases for VHL exon 1 mutation, exon 2 mutation and exon 3 mutation were checked by 2% agarose gel electrophoresis. Tumor grading was done by Fuhrman nuclear grading system and staging was done by pathologic TNM staging system. Fifty cases (80.65%) were VHL gene mutation positive and 12 cases (19.35%) were negative. VHL gene mutations were significantly associated with histological grades (p=0.005). Out of 62 cases, 24 cases were weakly positive (1+) and 38 cases were strongly positive (2+) VEGF immuno-reactivity. There was statistically significant association between VEGF immunoexpression and histological grades of clear cell renal cell carcinoma (p=0.00) as well as tumor stage (p=0.01). It was also found that VEGF immunoexpression of clear cell RCC was significantly associated with VHL gene mutation positive tumours (p=0.00). These results can be helpful in further invention of molecular targeted therapy for drug-resistant clear cell RCC patients.