In Familial Adenomatous Polyposis, a complex cascade of events leads from an initial mutation in a “gatekeeper” gene, eventually to a malignant tumor.

Many steps to cancer In Familial Adenomatous Polyposis, a complex cascade of events leads from an initial mutation in a “gatekeeper” gene, eventually to a malignant tumor. Bert Vogelstein, M.D. is a Howard Hughes Medical Institute Investigator and the Clayton Professor of Oncology and Pathology at Johns Hopkins University. His research focuses on the identification and characterization of genes that cause colon cancer. This has led to the discovery of the APC gene – the "gatekeeper" in colon cancer development. “Colon cancers provide a good example of a type of tumor in which the genetic steps leading from the normal colon epethelial cell to a cancer, are reasonably well known. And it's important to point out that this is not a speedy process, it generally takes 20 to 40 years to get from a normal cell to a malignant tumor; a malignant tumor is the same as a cancer, it's just another name. And the reason it takes that long is because it requires all these mutations and in cells that have intact repair systems, it takes decades to develop all these mutations sequentially. In a patient who has an defective mismatch repair system it takes a much shorter period of time, which is why patients with Non-polyposis form of colon cancer develop it at an earlier age.“ Bert Vogelstein, M.D., Johns Hopkins University: “The first step in the pathway is a mutation of APC; you could call this the gatekeeper gene. This is the gene that you have to get around – the cell has to get around – in order to eventually become a cancer; there's no way around that gatekeeper.” “But having a mutation there isn't enough to get a cancer; in fact it's probably not even enough to get a clinically symptomatic tumor. At most it causes a small benign growth, sometimes it's called an adenoma or a polyp.” “The next mutation that is known is one in an oncogene. APC is a tumor suppressor gene, the oncogene is RAS, it's generally an oncogene called K-ras, or another oncogene that the K-ras gene product interacts with called B-raf. And again, this is the idea that it's the pathway, it doesn't matter which gene, as long as they do the same thing. So, some tumors have a mutation in K-ras, others have a mutation in B-raf, but no tumor has both. “ “It wouldn't make sense to mutate both because they both do the same thing. And a cell that has acquired a mutation in those two genes is still a benign tumor but a little bit larger, now maybe a half an inch in diameter. But over time it will gradually grow and eventually acquire other mutations.” “There's another tumor suppressor gene called SMAD4 that is often mutated late in the benign process. There's another oncogene called PI3K that's mutated at about the same time, later in the process but still when tumors are benign.” “Finally a cell will undergo mutation in P53 and that mutation is very closely associated with the transition from a benign tumor to a malignant tumor.” Bert Vogelstein, M.D. is a Howard Hughes Medical Institute Investigator and the Clayton Professor of Oncology and Pathology at Johns Hopkins University. His research focuses on the identification and characterization of genes that cause colon cancer. This has led to the discovery of the APC gene – the "gatekeeper" in colon cancer development. “The only difference between a benign tumor and a malignant tumor is not the size, it's the ability of the malignant tumor to invade, to get through the tissues. A benign tumor stays put so the surgeon can cut it out easily. But in a malignant tumor the cells will invade underneath the layers that normally keep the epethelium away from the connective tissues underneath, and that invasion is what's bad, because they not only invade through those tissues in the colon, they can invade into a blood vessel or lymphatic and start a new tumor called a metastasis in the liver, or the lung, or elsewhere. And once a patient has disseminated metastases then they no longer can be cured by surgery, in fact, the tumors, the cancers in the place they started, in this case the colon, is never what kills people. What kills patients is always the metastasis that the surgeon can't remove.”

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