BETA - What are oncogenes and tumor suppressor genes and how do they work? Are these genes inheritable? How are they detected? What happens if there is a mutation in one of these genes?

In this Health Tree University lesson, we'll explore two key players in cancer development, oncogenes and tumor suppressor genes, and how they relate to myeloma care. Proto-oncogenes are normal genes that play a role in cell growth and division. Think of proto-oncogenes as the body's green lights for cell growth and division. Under normal conditions, they help cells grow at the right time and in the right amount. But when these genes become mutated, they turn into oncogenes, essentially stuck in the on position, causing uncontrolled cell growth that can lead to cancer. On the flip side, tumor suppressor genes act like the brakes of the cell cycle. They keep growth in check and help repair DNA or trigger cell death if something goes wrong. What if these genes get turned off or lose function, cells can grow out of control, again, increasing the risk of cancer? Maintaining the right balance between these genes is essential for healthy cell regulation. When that balance is disrupted, it can contribute to diseases like multiple myeloma. In this lesson, we'll break down how these genes work, what happens when they malfunction, and what that means for treating and managing myeloma. What are oncogenes and tumor suppressor genes, and how do they work? There's two big families of genes when we talk about genes associated with cancer development. One is what we call oncogenes. And then the second group would be the tumor suppressor genes. And we can think of this as, okay, what's an oncogene? An oncogene is a protein that if we make too much of it, or if we make a version of the protein that is stronger than usual, that will give the cell a survival advantage over others. Right? So if there's a mutation in an oncogene, that will lead to the cell having a better chance of surviving than other cells around it. Right? And that can lead to cancer development. Right? A cell that refuses to die when the body tries to keep it in check, that's a cancerous cell. The other side of the coin is these tumor suppressor genes, where let's say we're talking about DNA repair, genes that are involved in DNA repair. Right? For example, the BRCA genes. Right? The BRCA genes are proteins that have something to do, they're part of this machinery to repair DNA. Right? So when the protein is active and functional and healthy, it helps repair damage, errors in the DNA. If there's a mutation in the gene that makes that protein, the protein becomes non-functional or doesn't function as well, and therefore there can be more damage in the DNA. It's less able to repair an existing damage in the DNA. So it's two different ways. One is kind of giving the cell superpowers with oncogenes if there's a mutation. And the other one is basically stopping the cell from performing its normal mechanisms to prevent cancer. So if that happens, the cell will be more likely to generate new mutations and that can lead again to the cell not behaving normally. So that's kind of a little bit of a summary of what an oncogene is, what a tumor suppressor and how mutations in these types of genes can lead to cancer. And sometimes it can be an accumulation of mutations over time that leads to cancer development. And this is common in myeloma. We see perhaps the first hit would be a mutation in a tumor suppressor gene. And then the second hit is a mutation in an oncogene. The combination of those maybe pushes the cell from behaving in a more benign way, perhaps in a patient with say, MGUS, to behaving more aggressively, crossing that threshold to multiple myeloma. There are two groups of genes in cancer, oncogenes and oncosuppressor. Oncosuppressor, like the name, means that the tumor needs to suppress them. It needs to lose them. So that's the gene that are lost. So the gene 53, RB1, you know, on chromosome 13q, when we say on the Fischer report, RB1, 13q, that's an oncosuppressor. So they basically block the tumor. Oncogenes are the genes that the tumor needs. Cyclin D1, Cyclin D2, Cyclin D3, MAF, those are oncogenes. So the tumor needs to overexpress them, activate them. So KRAS. So that's why oncogenes are basically what the tumor needs to activate and tumor suppressor is what the tumor needs to downregulate. So if you think about this, all the alterations we reported, our group and others in the last five years or ten years, people have been longer than I in the field, they can easily be divided in loss of function and gain of function. Gain of function are oncogenes, loss of function are oncosuppressor or tumor suppressor. Are oncogenes and tumor suppressor genes inheritable? There are factors like genetic predisposition, of course, in myeloma. We know African-Americans have higher risk of developing multiple myeloma, for example. We still are trying to figure out why. We know there are some genes that have a germline. It means that it's basically a mutation present in your DNA that was edited by your father or your mom. And so all our body had that mutation, like the classic BRCA for breast cancer. So we don't have yet that kind of marker that say, oh, if you have BRCA, you have higher risk of cancer in breast and of iron in women. We don't have that. But we have like some small evidence, not small, but some evidence that there are these predisposition. There are families where myeloma is enriched. There are different studies published where they published this kind of predisposition. There is no unifying gene like in breast cancer. So we haven't found the BRCA of multiple myeloma. But the BRCA, for example, is a two-word suppressor. So the tumor needs to lose it. OK. So but the myeloma, there are like snips on cyclinine 1, which is 11, 14 translocation, which is in the Fisher report that seems to predispose patients to multiple myeloma. I think there are robust evidence that there is a predisposition. It's still unclear how we can use that in the clinical settings and how we can use that to identify the patients with high risk and eventually set up in a screening. If your mom had the BRCA mutation as a woman, you're going to get early screening when you are 20 or 30 according to different guidelines. And you don't just wait 40, 50 years old, right, because you could have caught much earlier or some patient had like preventive mastectomy. So there are like a lot of possible clinical options that are in guidelines or without guidelines. But in principle, we don't have that kind of knowledge, unfortunately, yet. There are different groups working on that. Hopefully, we will have some good data to use to implement our clinical practice. When we say about predisposition, it doesn't mean that you will develop cancer. So our body is like a machine that each human is a machine with different coordinates. And the coordinates are defined by our genetic background and from our environment. You know, you can have a predisposition to lung cancer, but if you never smoke, your risk might be even lower compared to a person without a gene that smoke two packs of per day. So the whole idea about predisposition is based on risk. So some predispositions increase the risk of meloma, but the risk is never 100%. You increase about 1%, 5%, 3%. And it's also very hard to estimate those risks because those risks are usually epidemiological or genetic, but never combined. Or it's very hard because if meloma takes 40 years to develop, I take samples from, let's say, African Americans living in Manhattan right when he's 60 years old. But he may have lived the entire life in the rural area of some Midwest state and was exposed to pesticides. And I never known about that. And I just said, oh, this guy's living in Manhattan. But he's not. His whole life was exposed to a completely different type of environment. So this type of data set, very well annotated with all the clinical information, not just about what you have done in the last two years, but like, you know, what your work, what have been done in your life, this type of things are very hard to collect, but I think are very, will be very informative for the future. And I know Health Tree is working actively to actually help the community to solve this and overcome these difficulties because this type of data set are really what the community needs to understand all these factors and not just stop to, who are you? What's your date of birth? That's it. How can you detect if you have mutations in oncogenes or tumor suppressor genes? The genetic alterations, the one that are present in every cell of our body, can be detected with whole genome sequencing. The oncogene in tumor, so basically you have your normal DNA or semi-normal according to all these NIPs and then you have the tumor, the tumor has all these chromosomal alterations, those can be detected in multiple different ways. You can go straight to your cyclinine 1 translocation, which is an oncogene, so a translocation that upregulates an oncogene. If FISH is just fine, KRAS mutation, you need the target sequencing. We believe that whole genome sequencing is better. The reason is that we know what we know, but there is a lot we don't know. And new therapies are also changing the concept of risk. Something that was high risk 10 years ago with DARA-VFD plus transplant might not be a risk anymore. And something that was neutral 20 years ago now is actually bad because downregulates C38 and DARA-2 works less. So the concept of risk change with the therapies. So that's why I think we don't have to just be happy with the targeted panel, which basically or FISH looking for what we know, but also trying to expand our knowledge with a more comprehensive way to get also what we, to put us in a position to be able to define what is unknown. What kind of testing would allow us to learn about the presence or absence of one of these mutations and, you know, are we doing it in clinical practice? Are we doing it in the setting of research? Right now, there are no clear indications or guidelines that would tell an oncologist treating a patient with myeloma to get next generation sequencing, right? Or, you know, to do a profile of the DNA of the myeloma cells. So that currently doesn't exist in guidelines. And at our center, you know, it's big institutions that are trying to really improve on existing treatments and go into precision medicine. How can we really tailor our existing treatments to the patients? We are doing this on a regular basis and we're trying to learn from that experience, right? So I think what more commonly people are doing, and this is true in the, you know, in community practices, you know, all across the country, is we are doing some version of this and that's really, we're doing perhaps a little bit less sophisticated ways of, you know, so for example, we've been doing karyotyping for a really, really long time, for many decades, right? Karyotyping is looking at the chromosomes of the cancer cell and trying to identify abnormalities in the chromosomes, right? So we're talking about mutations, but big mutations that huge chunk of DNA is lost, for example, right? A delusion or an insertion or a translocation, right? These are big, we call them structural abnormalities of the chromosomes. So that we've been doing for a long time. More recently, we started doing FISH, right? So FISH is a fluorescence in cytohybridization, right? So this is a more sophisticated way of approaching this, where we say, well, we know what the specific alterations are in myeloma that are associated with high risk, for example. So let's go looking specific with probes, let's go looking specifically for those. And we get a yes, no answer. Is this abnormality present or not? So when we talk about high risk abnormalities in myeloma, you know, delusion 17P, certain translocations, we are with FISH, we're specifically going to look for those mutations. Or yes, we call them mutations. It's a different kind of mutation. But now we're getting to the next generation of this, of doing this type of profiling, where we're going deeper. We're going at a gene level, right? So, yes, when you lose a big chunk of your DNA, you're losing many genes at a time, right? But what happens if we are, you know, that's not the situation, but there's just some change that happened at a gene level. Maybe that gene alone is the one that's no longer active or is hyperactive, right? So that you can only detect by doing these next generation sequencing studies, either from, you know, normally from a bone myeloma or aspirin, right, for a patient with myeloma. They can be done in peripheral blood as well, but that's for separate, for different reasons. Again, not being done as part of standard of care, but if you go to any major institution to get treatment, it is likely that they might do some form of this testing. And that will, you know, we work with companies that do this, right? And there's a long list of companies that do this kind of testing. They're never, you know, because there is no clear indication to do this in myeloma, most of them don't have a specific myeloma panel, right? They have a panel that they use for other gene, for other cancer types that they can adapt to or tailor to a patient with myeloma. And that is ever evolving, right? As more data comes in and we say, well, this gene might actually have some significance in myeloma, right? Let's say, for example, the BCMA gene, right? When we talk about a lot of the novel treatments in myeloma are BCMA-directed therapies, right? So what does it mean if a patient were to have a mutation in the BCMA gene? Maybe that's making it more likely that they will respond to a BCMA treatment or less likely, right? So that has certain implications and we have to start looking at that. And as we produce more research, that will make its way to the clinic and more widely, it will become more widely available. So that's a long answer, but it's how we are approaching, you know, incorporating these genetic. Do we have any drugs that can target oncogene and tumor suppressor gene mutations in multiple myeloma? Yes, we do, but not approved for myeloma specifically, right? So let me give a clear example. This is where we start to borrow from what we know from other cancers and try to use that to treat our patient in front of us with myeloma. To give a good example would be something like breast cancer, right? Where the BRCA mutations are very well known to cause predisposition and, you know, to increase the risk of developing breast cancer. Over time in the breast cancer space, they've managed to create drugs that can use that vulnerability of the cancer cells having this mutation, right? In a way, it leads to an advantage, but it also can be like an Achilles heel, where if you know how to address it with a drug, you can actually exploit that and kill the cancer cell more efficiently without harming other cells. So they've been using drugs called PARP inhibitors, right, to treat breast cancer that has these specific BRCA mutations. That has moved on to other kinds of cancers where the BRCA mutations are common. Lung cancer, pancreatic cancer, in some cases prostate cancer. So it starts out with one cancer type, but then it starts to permeate to other kinds of cancers, right? So when we think of, there are many, many examples that we have here at Mount Sinai where we've identified a patient having some mutation in a particular oncogene or tumor suppressor and we've borrowed a drug from essentially from a different cancer type and have used it successfully to treat that specific patient, right? A different patient would not have responded to that drug, but in this case, we can exploit that vulnerability. So we have a precision medicine protocol that's active here where we are doing exactly this. We're profiling at a very, very deep level the genetics of the myeloma cells of a patient. Perhaps this is more indicated for a patient that has very advanced myeloma, that has not a ton of options for treatment. We're doing this deep profiling to identify potential vulnerabilities that we can target even outside of what's usually in our menu of drugs that we can use for myeloma. So we do that quite a bit. In some cases, it can be very successful. Are there any oncogenes associated with multiple myeloma? So oncogenes are genes that are oncogenic, meaning they cause cancer. One of the most famous oncogenes is MYC. It was one of the first described by Harold Barmas, who won the Nobel Prize for that. He found it in chickens. It turns out to be an incredibly important oncogene in multiple myeloma. We think it's one that is associated with the progression from the benign disease, monoclonal myelopathy of undetermined significance, to multiple myeloma cancer. Not in all patients, but in a fair number of patients. There are other oncogenes. There's quite a few oncogenes. The important ones in multiple myeloma are cyclin D1, cyclin D2, and cyclin D3. MAF, MAF A and MAF B. FGF receptor 3 and MN-CET. Those are the genes that are located at the chromosome translocations that we talked about earlier. And then of course, MYC, NRAS, and KRAS. Those are probably the most important oncogenes in multiple myeloma. What tumor suppressor genes are associated with myeloma? TP53 is a protein that is essential, perhaps the most essential protein in protecting cells from cancer. So when the protein is inactivated, whether because the gene was deleted, right? A big chunk, like the lesion 17p, a big chunk of the chromosome was lost. We lost a copy of TP53. We lost a protection mechanism in that cell. Or it could be that there's a mutation in the gene that makes the protein less active. So TP53 is a tumor suppressor gene. Thank you for listening.