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.

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.”

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