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New Treatments for Molecular Genetics

We are going to take you through some elementary aspects of carcinogenesis and then turn to oncogenes and tumor suppresser genes. I’ll define those terms for you. I’ll give you some key examples of cancer types that are associated with these types of genes, and also give you some conceptual basis of how they are activated or inactivated. I’ll also describe a number of genetic diseases that predispose to cancer.

So we’ll start with the first slide. When normal cells are exposed to environmental chemicals, radiation or viruses, this can lead to a series of genetic and epigenetic changes that eventually lead to clinically evident cancer. This usually takes 20, 30, sometimes 40 years and eventually this clinical cancer is manifested with metastasis. Well, what’s going on during this long process? Well, among other things, there is activation of proto-oncogenes and inactivation of tumor.

So let’s first turn to oncogenes. This shows you a pathway of signal transduction and in this very complicated pathway there is one very common oncogene that’s called the ras oncogene. So I want to make a couple of points here. One is, when you think of oncogenes or tumor suppresser genes, not only think of them as single entities but components within a pathway. The second is that the ras oncogene is activated by mutations, missense mutations leading to amino acid.

Now another mechanism for activation of oncogenes is not by a mutational mechanism but by gene amplification. So you have additional copies of the gene and the myc family of oncogenes is a prime example of this and myc amplification.

A third mechanism is one that is probably quite familiar to you and that’s by chromosomal rearrangements and translocations, including the quite famous Philadelphia chromosome, which is a translocation of chromosome 9 and 22 in which abl, which is a kinase, is activated by a promoter called BCR which, within the genome in this translocation, gets put in the wrong place. It gets put right in front of the abl gene. So then it is constitutively expressed.

Now you might think that the idea of oncogenes and tumor suppresser genes is one that is relatively new but one can go back to the turn of the century when Bouvier wrote the following, "The unlimited tendency to rapid proliferation in malignant cells could result from the permanent predominance of chromosomes that promote division." Substitute oncogenes here.

This is Bouvier, this is his high-tech instrument here, a microscope. He was a basic scientists and also a clinical investigator and he was interested in sea urchin eggs and something called dispermine, which two sperm impregnate an ova here and you get abnormal chromosomal segregation and aneuploidy, which means an abnormal number of chromosomes. So some of these ideas go back quite a long time.

Now chromosomes can get mixed up in several different ways. The diploid number of course is 46. If you have spindle pole errors, and there’s usually two spindle poles but sometimes there are three or four associated with particularly with inactivation of tumor suppresser genes, you’ll get tetraploid and even larger numbers of chromosomes. If there’s a spindle error and there are

Now one of the classic types of tumor suppresser genes is associated with retinal blastoma. Retinal blastoma, as all of you know, is involved in a particular type of cancer in the eye in which the retinal blastoma gene is inherited, in this case, from a father. The mother has normal genes, the kid has one normal gene and one abnormal gene and you can get reduction of homozygosity by a number of different mechanisms. One is what’s called non-disjunction and you lose the

A quite interesting way of inactivating tumor suppresser genes is by oncogenic viruses. And this is a partial list of oncogenic viruses that you are familiar with including the hepatitis viruses, Hepatitis C of course is becoming rampant in the United States and is leading to an increase in the risk of developing hepatocellular carcinoma, and you are going to see much more liver cancer due to Hepatitis C. Hepatitis B, there’s good vaccination for that and that is actually a

There are a number of common cancers with the familial subset. This is usually only a few percentage although in the press there is a lot of news and your patients come to you and say, "Well, do I have a genetic predisposition to breast cancer?" or something else. And in some cases they will but in fact, most of the time the cancers are sporadic and are not due to an obvious germline mutation in a specific gene. I’ll discuss more about BRCA1 and BRCA2 in a few moments, which are involved in familial breast and ovarian cancer. This is the kind of

Now let’s turn to colon carcinogenesis. The changes that occur, both genetic and epigenetic changes, during colon cancer formation have been worked out perhaps the best of any type of cancer that I’m familiar with. In which you have a normal colon and mutations in the APC gene, which is a tumor suppresser gene or beta kintenin (?) which is a tumor suppresser gene, will lead to hyperplasia. And this occurs not as a germline but due to some cause in the environment or

One of the genetic diseases that predispose to cancer is described here. These are actually not atomic bomb blasts but this is part of an individual’s colon with familial polyposis and these are multiple polyps. In fact these individual’s - I had the opportunity to take care of one of them - have thousands in general, of polyps in their colon and it’s inherited in a recessive way. These

Mechanistically what’s going on? Well, normally there is a single transduction pathway. This one doesn’t involve ras but it involves the APC gene and the beta kintinen gene and others. And what the APC gene product does is actually capture the beta kintinen protein and keeps it in the cytoplasm. When it is translocated in the nucleus it acts as a transcription factor and it up-

Now genomic instability is a term that is frequently used. Genomic instability can mean aneuploidy, abnormal chromosomal number, chromosomal rearrangements - like the Philadelphia chromosome and activation of abl - focal deletions, focal amplifications which can lead to myc gene increased copy number, mutability and unstable repeated sequence. I’d like to turn to these two because it is another example of a defect, in this case in DNA repair, that can lead to colon cancer. This has a name. It’s called hereditary non-polyposis. So there are not a

What happens with … or what genes are involved with the mismatch repair? Mismatch repair means that as the genes have alterations in them, then they are not repaired normally. So these are predisposing to mutations in other genes. What other genes might be involved? Well, genes include the TGF-beta receptor and this is a negative growth factor pathway. So it stops cells from growing. So mutations in this receptor lead to a lack of this growth control. Another gene that is frequently mutated in these individuals with hereditary non-polyposis colorectal cancer is called BAX. That’s a gene that’s involved in cell death, apoptosis or program cell death. So

So let’s define gatekeepers. Again, this is a conceptual term that Kinsler and Vogelstein came up with a couple of years ago. Gatekeeper genes: these tend to be predetermining and if there are mutations in these genes it leads to a high risk of cancer with the hereditary mutation. They directly regulate the growth of tumors by inhibiting growth or promoting death. Cell type

Caretaker genes are predisposing so they do not have a direct effect but they predispose to the development of cancer and have a moderate cancer risk with people carrying the hereditary mutation. They are inactivated, and this does not promote tumor initiation or early development directly, but leads to genomic instability - which I mentioned earlier - resulting in mutations in all genes including the gatekeeper genes. Examples of this are xeroderma pigmentosa group C, or XPC that’s involved in some cases of sunlight-induced skin cancer. Kids who inherit these

This is a list of some of the tumor suppresser genes associated with human cancer: P53, which I’ll discuss in a moment, that’s involved with many different kinds of cancer, the RB gene that’s responsible for retinal blastoma, has a germline mutation, but somatic mutations due primarily to