Studies of inherited cancers thus often shed important light on the causation of the non-inherited counterpart disease. Study of these ‘cancer families’ helped identify key cancer-related genes such as APC, RB (linked to retinoblastoma, a rare childhood eye tumour), p53 (linked to Li-Fraumeni syndrome, in which patients develop multiple different cancers), and VHL (linked to von Hippel Lindau syndrome, a complex disorder that includes kidney cancer). In addition, examination of the varying natural history of the inherited disease helps us to understand what the normal function of these genes may be. All of the genes mentioned above are termed ‘tumour-suppressor’ genes, but this is a misnomer as this is not their primary role in the organism. As may be predicted from the APC gene, these genes are key regulators of the cell cycle (the first two aspects of the hallmarks mentioned above), and damage or deletion of function leads to uncontrolled growth. Examining the normal functions of these genes have shed important light on how the cell cycle is regulated. As lack of control of the cell cycle is a hallmark of cancer, many cancer treatments work by interfering with the cell cycle genes that are misfiring in the cancer cell. In addition, a new generation of cancer drugs, the targeted molecular therapies, is currently hitting the clinics and the news headlines. These drugs work by targeting specific molecules known to be misfiring in cancer.
Not all inherited cancer genes are directly involved in the cell cycle, however. A good example is the VHL gene, originally identified in patients with von Hippel Lindau syndrome. Sufferers develop multiple abnormalities from an early age, including cysts in the nervous system, in particular, the cerebellum (part of the brain involved in balance and coordination), spinal cord, and retina, together with kidney tumours both benign and malignant. The kidney tumours are typically bilateral, multiple, and occur from a young age. As for APC, the patient inherits one non-functioning gene; a single hit to the remaining gene leaves no functioning VHL protein in the cell. Given that renal tumours are relatively rare but are common in patients with VHL, this tells us that the chances of a given gene suffering one hit are relatively high, but suffering two hits takes much longer, hence sporadic tumours are single and have a much later age of onset.
Detailed study of the VHL gene has revealed that it is involved in sensing the oxygen levels in the cell. If oxygen is low, this leads to the production of signals to surrounding cells to start growing new blood vessels. In other words, it regulates angiogenesis, a key hallmark of cancer. Further studies have shown that these changes are sufficient to drive the cancer cell in the test tube, and the replacement of the VHL gene in these models will reverse the cancerous characteristics of the cells. Furthermore, the kidney tumour type found in VHL patients, called renal cell carcinoma, is characteristically very rich in blood vessels, as may be predicted from the gene function. Study of sporadic (non-inherited) renal cell carcinomas has revealed that VHL is mutated in around 70% of cases, making the VHL/angiogenesis pathway an attractive target for therapy. Research into new VHL-based treatments for kidney cancer, a notoriously difficult cancer to treat once it has spread, has proved very fruitful, with six agents licensed since 2006 and several more pending for a disease for which only two agents had been licensed in the previous 25 years. All of these agents target aspects of the pathway identified by the genetic research summarized above.