Introduction to Tumor Suppressor Genes and Their Protein Products
The other critical step in tumor initiation and progression, beside the activation of oncogenes, is the inactivation of tumor suppressor genes. Under normal function, a tumor suppressor gene (TSG) acts as a negative regulator for cell growth control by limiting cell proliferation and tumor development. For tumors to develop, it was found that both copies of the TSG must be lost either through mutation or deletion of the gene (1). It is not the TSGs themselves that limit cell growth, but it is the regulator proteins that they produce. The regulator proteins produced are involved in inhibiting cell production and survival. With the loss of TSGs and lack of regulatory proteins, the tumor progression can eventually lead to many types of cancer.
Overview of VHL Disease
The von Hippel-Lindau disease is an autosomal dominant inheritance disorder that is associated with the loss and mutation of VHL tumor suppressor gene (2). VHL disease is a hereditary cancer that appears in 1 in 36,000 live births. Germline VHL gene mutations of this rare disorder are a predisposition to many cancers that can produce benign or malignant tumors due to a loss of the wild-type VHL allele given by the unaffected parents (3). Such tumors can be renal cysts and renal carcinoma, central nervous system hemangioblastoma, and phaeochromocytoma. Pancreatic islet cell tumors, gonadal tumors, endolymphatic sac tumors, broad-ligament cystadenomas have also been mentioned in relation to VHL disease (4). These tumors are found in a vast number of organs including the kidney, retina, CNS, pancreas, and adrenal gland. However, the majority of the cases for VHL disease involve renal cell carcinoma (3). Figure 1 depicts the prominent locations of the tumors as well as its hereditary nature. With these tumors come hypervascularity and high levels of vascular endothelial growth factor and hypoxia inducible mRNAs (5).
Figure 1: A) Locations of the tumors caused by VHL disease. B) Family pedigree showing the dominant inheritance of the disease for various VHL tumors (6).
There are two types of VHL; type 1 involves a whole or partial gene deletion or nonsense mutation with a low risk of developing phaeochromocytoma. Type 2 is subdivided into three categories, type 2A, 2B, and 2C, all of which undergo a missense mutation (4). Since most forms of the disorder involve a slow onset of symptoms, most diagnoses do not occur until 4 to 5 years after the onset of signs. Type 2A has a low risk for renal cell carcinomas while type 2B has a high risk and type 3A deals with no other neoplastic factors aside from dealing with pheochromocytomas only (7).
The VHL Gene and Protein
To better understand human carcinogenesis, some researchers have focused on tumor suppressor genes and their significance. In 1988, the VHL gene was identified through linkage analysis and chromosome mapping and later it was isolated in 1993 (8). The VHL...