Vogelstein Discusses Gatekeeper Genes, Caretaker Genes

NEW ORLEANS--Mutations in two types of genes, gatekeepers and caretakers, help explain both the progression of cells from normal to cancerous and the mechanism of actions of effective antitumor drugs, Bert Vogelstein, MD, of Johns Hopkins University School of Medicine, said at the plenary session of the 89th annual meeting of the American Association for Cancer Research.

"Gatekeepers" are the genes that absolutely must be inactivated before a cell can become cancerous. Tumor suppressor genes are examples of gatekeepers. "Caretakers" are genes involved in maintaining genetic stability and minimizing the rate at which mutations occur in gatekeepers.

Dr. Vogelstein used familial colon cancers to illustrate how defects in gatekeeper genes and caretaker genes can lead to cancer. He said that about 20% of colon cancers appear to be inherited, and these inherited cancers are of three types: high penetrance, medium penetrance, and low penetrance.

An example of high-penetrance familial colon cancer is familial adenomatous polyposis (FAP), which is caused by a mutation in the APC gene. APC is a gatekeeper gene that acts to suppress tumors. When it is inactivated, hundreds or thousands of polyps form in the colon, and some inevitably will progress to cancer if not removed.

More subtle mutations in the gate-keeper APC gene may underlie at least some familial colon cancers with low penetrance. The so-called "I1307K permutation" in Ashkenazi Jews is an example. A mutation in the APC gene at codon 1307 leads to a string of eight adenines in a row, an unstable sequence.

This mutation is found in 6% of healthy Ashkenazi, in 12% of those with colon cancer, in 17% of those who developed colon cancer before they were 65, and in nearly 30% of those with family histories of colon cancer.

‘Large Chunk’ of APC Deleted

"This instability, arising from this run of A’s, often causes the insertion of an additional A or a mutation at surrounding sequences," Dr. Vogelstein said. This second change then causes deletion of a large chunk of the APC protein.

"One has to wonder whether other subtle mutations in other gatekeeper genes account for some cancer susceptibility in other diseases, including other colonic predisposition syndromes," Dr. Vogelstein said. Many variants now considered to be polymorphisms may, in fact, be subtle premutations, he said.

Hereditary nonpolyposis colon cancer (HNPCC), also known as the Lynch syndrome, is an example of a medium-penetrance cancer caused by a mutation in a caretaker gene. In contrast to FAP, patients have only a few polyps, but each polyp has a high risk of becoming cancerous.

"The syndrome is caused by defects in mismatch repair, one of the repair systems responsible for fixing mistakes that occur during DNA replication," Dr. Vogelstein said. As a result, the mutation rate in tumors from patients with HNPCC is very high.

FAP patients, who have a gatekeeper gene defect, have accelerated tumor initiation, but normal tumor progression (20 to 40 years). HNPCC patients, who have a caretaker gene defect, have normal tumor initiation, but accelerated tumor progression (3 to 5 years). Despite these two very different defects with two very different mechanisms, the result in one way is the same, he said: The patients develop colon cancer at a median age of 42 years.

Another common feature of colon cancer is genetic instability (a feature, Dr. Vogelstein argued, that should be added to the model of how colon cancer develops). The genetic instability in HNPCC, he said, is caused by the mismatch repair defect, which allows mutations to accumulate rapidly.

In most other colon cancers, there appears to be a different kind of instability attributable to a defective mitotic checkpoint gene, Dr. Vogelstein said. A checkpoint gene is one that keeps chromosomes from dividing until all have lined up appropriately.

There are probably dozens of checkpoint genes, he said. When there is a mutation in a checkpoint gene, chromosome replication can go awry, and daughter cells can end up lacking pieces of chromosomes. Over time, non-HNPCC tumors lose a third of their chromosome arms.

Dr. Vogelstein concluded by making the argument that all current anticancer drugs that cause remission or cure work in just one way: "They exploit the fact that checkpoints of one form or another are defective in cancer cells. That’s the reason some cancers are more sensitive to these drugs than normal cells."