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Causes, Inheritance

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All cancers are genetic, in that cancers are caused by genetic mutations in genes that lead to malignancy.
Transcript:
All cancers are genetic, in that cancers are caused by genetic mutations in genes that lead to malignancy. However, about 10% of cancer patients inherit a genetic defect conferring a susceptibility to cancers over their lifetimes. Click on the buttons to the left to find out more about inherited colon cancers. Cancer gene types A cancer gene alters the normal functioning of a protein. There are three major categories of cancer genes. 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. “Cancer is in essence a genetic disease. It's caused by mutations of genes and there are three kinds, three types of genes, that contribute to cancer. The first is called oncogenes. These are genes that normally signal cells to grow. And when an oncogene is mutated, the cell continues to grow even though normally it wouldn't. A good analogy for an oncogene is the accelerator in a car. And a mutation in an oncogene is like having accelerator stuck to the floor, car keeps going even though the driver takes his or her foot off it. Cell keeps growing even though it's not receiving the signals that would normally drive cell growth. Second class is called tumor suppressor genes and these are the brakes of the cell. And just as cars have more than one brake, they have a foot brake and they have a hand brake and you can even take the keys out of the ignition if all else fails. Cells have more than one brake, more than one tumor suppressor gene. And it's the combination of mutations in oncogenes and tumor suppressor genes, sequential accumulation of those mutations, that eventually results in a full-blown cancer. Now there's one other class of genes, which contributes to cancer, this class is called stability genes. They don't directly control cell birth or cell death, that is they don't directly impact net cell growth. What they do is simply control the rate of mutation. So if one has a defective stability gene, then all genes are mutated more frequently, including oncogenes and tumor suppressor genes, so the whole process is accelerated. And a good analogy for a defective stability gene is having an inept mechanic work on your car. It keeps getting worse.” “Cancer is in essence a genetic disease. But it's really quite different than all the other genetic diseases that people usually think of when they think about a genetic disease. For instance cystic fibrosis: cystic fibrosis is always caused by a mutation in a single gene. People who get that mutation generally get very similar symptoms. One mutation gives you the disease. Cancer's not like that. No single mutation results in cancer. It's an accumulation of mutations in both these brakes and in the accelerators. You have to dismantle, basically, many of the controlling elements in the cell, to get to a cancer. If you just dismantle a few of them you might get a benign tumor, but you won't get a cancer. It's only when all of these pathways, or many of them, are inactivated that a cancer results. So it wouldn't be correct to say that a given mutation and a given gene causes cancer, what you can say is a given mutation contributes to the development of cancer.” Colon Cancer Familial colon cancer was long thought to be inherited; however a complete understanding of its causes awaited the discovery that specific genetic mutations confer a large increase in susceptibility to these types of cancers. Bert Vogelstein, M.D., Johns Hopkins University: “Colon cancer is the type of cancer that we study at our lab, that we focus on in our lab. It kills in the United States, about, close to 60 thousand people a year. It occurs in roughly 150 thousand people in the United States alone each year. In the world at large, it easily occurs in over half a million people, so it's one of the most common cancers, unfortunately, both in the United States and in the world.” “Most colon cancers are not hereditary, in the sense that if you ask a patient with colon cancer if anyone else in their family had it, they'll say no, or maybe just one distant relative... if you see many members of a single family with colon cancer, especially if they've developed cancer at an early age, then there is a high likelihood that there is some defective gene that's being inherited in the family.” “And I might expand on that and just say the average age of development of colon cancer in the general population is about 67, but in these families who are predisposed to cancer, you often see patients who are in their 40s, 30s, we've even seen children 8 or 9 years old who developed colon cancer in these particular families.” “Most colon cancers are not hereditary in the sense that if you ask a patient with colon cancer if anyone else in their family had it, they'll say no or maybe just one distant relative. But in about 5% of people, one in 20 with colon cancer they will say that lots of relatives in their family had it.” “There're two major forms, one's called FAP, which stands for Familial Adenomatous Polyposis, lets call it polyposis for short. And the other one is HNPCC, which stands for Hereditary Non-Polyposis Colon Cancer; we'll call that one Non-polyposis.” “And the two syndromes are quite different even though, in both, patients who are members of these families often develop cancer at an early age, in the Polyposis families the patients have thousands of benign tumors all throughout their colons. Whereas in the Non-polyposis cases they don't have any distinguishing features, they just tend to get colon cancer and a few other cancer types more commonly than one would expect.” “The gene that caused the polyposis form; that's a gene called APC. And that gene is a standard tumor suppressor gene; it's a break, and when it's inactivated by mutation then it causes, or contributes, one initiating step to cancer. “ “In fact, in a cancer, a colon cancer that occurs in the general population, non-familial form, the first mutation, the absolute first mutation that occurs in that cell, which will eventually become a tumor, is a mutation of the APC gene. The only difference in the familial form is they inherit a mutation in the APC gene and that's why they get so many tumors and so early; they have it in all their cells, not just in a single cell.” “The other form of inherited syndrome the Non-polyposis, turned out to be due to a completely different mechanism, it was due to defects in stability genes. And, in particular it was due to defects in any one of several genes that control mismatch repair.” “Mismatch repair is one of the three major systems that cells use to repair DNA. DNA is always, normally, in the process of acquiring occasional mutations. Each time a cell divides, one mutation, on average, occurs. Now usually that mutation isn't in an oncogene, or a tumor suppressor gene, or in a position of any gene that causes the cell a problem.” “But if it occurs in a cancer gene of any one of these three classes, and if it occurs in the germ line, it can lead to a hereditary predisposition. And patients with the Non-polyposis form of hereditary colon cancer have mutations in one of the mismatched repair genes.” 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. “APC is expressed in all cells. We don't know why it only causes cancers when mutated in the colon and in a few other places. We can speculate, and it really is speculation, that it does something a little bit different in the colon than in other tissues, but we really don't know that. It's even harder when you talk about mismatch repair genes, because we know exactly what mismatch repair genes – these genes were discovered in bacteria and have been studied in lower organisms for years and they do the same thing on every cell of the planet, and I literally mean every cell of the planet. They repair mistakes that are made as cells synthesize their DNA. Now why those – why a defective mismatch repair system should only lead to cancers in the colon and in the uterus predominantly, no one has the foggiest idea, and I can't give you any answer that I think even makes sense.” 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.”
Keywords:
tumor suppressor genes, bert vogelstein, howard hughes medical institute, cause colon cancer, hughes medical institute, howard hughes medical, colon cancers, johns hopkins university, cancer genes, apc gene, tumor suppressor gene, genetic mutations, colon cancer, cancer development, cancer gene, foot brake, cancer patients, genetic defect, oncogenes, genetic disease
Creative Commons License This work by Cold Spring Harbor Laboratory is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States License.

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