What do I need to know about deletion of 17p?

In this Health Tree University lesson, we'll dive into key questions about 17p deletion in multiple myeloma. A 17p chromosome deletion refers to the loss of all or part of the short arm of chromosome 17. Join us to explore the answers and gain a deeper understanding of this important genetic abnormality. What is a deletion of 17p? Why is deletion 17p considered high risk? On the 17th chromosome, on the short arm, which the short arm of the chromosome is the p arm and the long arm is q, there is a gene called p53 and it is responsible for DNA repair. The TP53 gene provides the instructions for making the p53 protein, which is responsible, for DNA repair. So when the genetic material in a cell is damaged, p53 repairs that DNA. When p53 is gone, p53 deletion, or the whole chromosome 17 is gone, minus 17, or the short arm of chromosome 17 minus 17p is gone, you've lost the ability to repair DNA. The TP53 gene makes the p53 protein the guardian that keeps cell growth in check. When it's altered, myeloma can become harder to treat. Learn more about TP53 gene abnormalities in Health Tree's chromosomal and gene abnormalities course. Now all chromosomes come in pairs, so there's actually two copies of 17 and you can lose one or both. One moderately impairs DNA repair, one severely impairs DNA repair, but our cells are constantly being bombarded by free radicals and oxidants that cause DNA damage and p53 repairs that DNA. And if you're missing it, you can't repair the DNA and that leads to genetic instability, which results in more aggressive cancers. So we talk about minus 17p being prognostically adverse, severe, in multiple myeloma, but the same is true in leukemia, lymphoma, chronic lymphatic leukemia, minus 17 is bad for all forms of hematologic cancer. Can only a percentage of your cells have the 17p deletion? Can that percentage change over time? So 17p deletion doesn't have to be in every single myeloma cell and in fact most of the time it's not. It's usually in a small percentage of the myeloma cells. So for people who have had 17p deletion in the very beginning, what we might find is that there's a smaller percentage of the myeloma cells having 17p deletion, but that percentage grows over time. And why might that be the case? Maybe the initial therapy that we received or that the patient received actually got rid of the cells that were more easy to eradicate, but then the 17p population grew over time. Or maybe the 17p deletion was acquired, meaning something happened and changed within the myeloma cell so that now it acquired a new mutation and then that's why it's growing. Whenever we do chromosome analysis in multiple myeloma cells, we try to look for mutations that we know are associated to multiple myeloma. And the studies that we do, whether it be karyotyping or FISH or gene expression profiling, are going to give us results of whether that gene mutation is present or not, but it also has the ability to determine out of the number of cells that the study analyzed, what percentage of those cells have that specific mutation. So for example, let's talk about 17p deletion. We associate 17p deletion to high-risk disease and a very aggressive type of multiple myeloma. But having the mutation alone, just knowing that you have that mutation, is not going to give us the whole picture. It's important to know what percentage of the myeloma cells in your body have this mutation so that we can have a better idea of if this mutation is going to really have an impact in the patient's survival and in the response to therapy or not. So whenever we do FISH studies, the genetician who does the study takes a group of myeloma cells, analyzes those cells, and then gives us a report saying, we did find this mutation, let's say 17p, and we saw it in this percent of all the myeloma cells. And it will give us a percentage, whether it's 5%, 10%, 40%, 50%, 80%, or none. Sometimes we will see mutations and the labs have a cutoff value that below that percentage it's considered negative and above that percentage it's considered positive. That's important for the reports, but in addition to that, they also tell us if it is positive, how many of the myeloma cells are containing that mutation. Knowing what percentage of the myeloma cells have a specific mutation is important because that can help us determine the prognosis or guide us in the prognosis of the patient. So talking about 17p deletion, if we do FISH on bone marrow biopsy from a myeloma patient and we see that they have a 17p deletion, and the report of the FISH tells us that it's only 20%, that is going to behave very differently than somebody with multiple myeloma who has a bone marrow biopsy, and the FISH result says that they have 60% involvement with 17p deletion. And the same thing applies for other mutations and translocations. It all depends on how penetrated these abnormalities are in all of the myeloma cells that your body has. What is the cancer clonal fraction or clonal burden? So when we think about myeloma, it is a very heterogeneous disease. There are a lot of different clones and as the disease gets more advanced, there are more clones that usually develop. What that means is that as the cells mutate and change, some cells may have some genetic changes and other cells may not. And so the percentage of cells that have a certain mutation is called the cancer clonal fraction or the fraction of cells that are part of that clone with that particular mutation. So for instance, with 17p deletion, when we talk about high risk being more than 20%, when we do the test called the fluorescence in situ hybridization on the bone marrow tumor cells or plasma cells, we're looking for more than 20% of those cells to have the mutation to consider it high risk. If a greater percentage of your myeloma cells have 17p deletion, are you at a greater risk? When the study and the results show us the threshold of 20% as the cutoff for high versus standard risk. But I think that remember everything is often a continuum and so a higher percentage in warm and suggest higher risk. The more cells that have minus 17p, the worse it is. If 80% of the cells have minus 17p, it's going to be worse than 10%. But when physicians communicate and when we discuss it with patients, we can't talk about 10 versus 15 versus 30 versus 40. So we have to determine cutoffs where we decide this will be bad. And so for example, 30% is a commonly used cutoff for minus 17p. But it's really silly if you think that someone who has 32% is going to do worse than someone who has 28% because it's nuanced. But for the purposes of reporting outcomes, so all the doctors agree on what they're talking about. We have to establish thresholds. And there's recently been an argument for 17p, 15%, 20%, 30%. And so understand that these are recent adaptations based on acquisition of new information. But any 17p isn't very good. Higher is worse. 20% and 30% are currently in competition for what we should be reporting out as high risk. Besides clonal burden, the percentage of myeloma cells with a 17p deletion, allelic burden must also be considered. What does this mean? So 17p is complicated because there's the clonal burden and the allelic burden. So what does that mean? Clonal burden is if you have a bunch of myeloma cells, what percentage of cells have that abnormality? And so initially, some studies would say you need 60%. Others said any amount. Now we seem to have coalesced around 20%. So if 20% of your myeloma cells have that deletion, that's considered high risk. Then the other part of it is the allelic burden. It's not how many cells have it, but within a given cell, you have two chromosomes. And are you missing it on one or both? And so that's monoleilic or bioleilic. So that also matters. And are they mutated or not? And that requires the next-gen sequencing to do. Can someone with 17p deletion have a good outcome? When we think of mutations, we always get worried about hearing that we have a mutation. And when we do bone marrow biopsies or bone marrow aspirates or sample tumors, we look for mutations to have a sense of whether this cancer might have a tendency to be aggressive or easier to treat or something that we can actually target. And 17p deletion is one of those mutations that for a while now we've associated with a poor prognosis or more aggressive type of disease. And it can mean that it's either hard to treat and not be able to achieve a good response, or that even if we do achieve a good response, that it tends to come back sooner and we're going to have to be dealing with relapses. But one thing to keep in mind is having the mutation doesn't necessarily mean that you already are doomed. There are several things that need to play into this equation. One is what percentage of all the cancer cells have the mutation. It's very different to say that only 3% of the cancer cells have this mutation than to say 80% of all the cancer cells have the mutation. Because in myeloma, it's not everything the same. We have subclones or subtypes of myeloma cells, depending on how, when they're dividing, what mutations they develop. So if we do have a mutation, it doesn't mean that all of the cancer cells are going to have that mutation. So the percentage of the cells that have that is one factor. The second factor is are there other mutations that are found in the cancer cells as well? Recently, we had the IMS meeting where we proposed the new high-risk mutations. And up until now, we were associating 1Q deletion, a 17P deletion, translocation 414, 1416 as poor prognosis. But now we're realizing that it's not quite that way. And you have to have more of an association of having a 1Q deletion and something else that it's going to really give you that high-risk or poor prognosis or harder to treat. And the third thing to keep in mind is you might have a mutation, but that doesn't mean that that mutation is going to be manifested. So when patients ask me about that, I try to associate this to the 23andMe test that we could do at home. That I don't know if it's still available or not, but everybody was going through the craze of, oh, I want to know what my 23andMe is to kind of have a sense of my ancestry, but at the same time if I have a predisposition to Parkinson's or to diabetes or things like that. In that test, I told you, okay, you have these changes or these mutations that can predispose you to Parkinson's or that can predispose you to these medical problems. But it doesn't mean that you're actually going to have them. You have a predisposition. And the same thing happens with cancer in my lung. If you have 17P mutation or deletion, it doesn't necessarily mean that it's going to really act up and cause the problem. It has the tendency to or it has a predisposition to it. But those are the three main things that we need to keep in mind when we're thinking about a mutation. So this is very important because when we talk about any prognostic factor, beta-2 micro-globulin, LDH, extra medullary, high risk fish, minus 17P, these are statistical estimates of outcome. So that doesn't mean that every person with it will do poorly and every patient without it will do well. These are averages. So if we take 500 patients with minus 17P and compare it to 500 patients without 17P, okay, the people who have the minus 17P will do worse on average. But when we play average games, statistical games, I can tell you with absolute assurance in the United States that the average man is taller than the average woman. But if you were blindfolded and you tapped a woman on the street, don't bet your house that she'll be shorter than you because you're going to lose your house periodically. On average, you'll be right. So averages give us guidance of what the tendency will be, but it doesn't when we drill down to the individual patient, it doesn't put them in a box because patients can be minus 17P, I've got them, they're out 20 years. Obviously there are other factors we don't understand. And there are plenty of people, unfortunately with my alumna without 17P, who haven't had a very lucky course. Can the 17P deletion go away with treatment and not come back at relapse? That would be fantastic. But I don't think that is what we think occurs. When somebody has 17P deletion, always in our minds we think that it's always there. We might, for instance, do a bone marrow biopsy and not find it if there are no myeloma cells there, meaning if we've achieved a deep response and MRD negativity, etc. If we did a bone marrow biopsy in that patient and looked for 17P deletion, we might not detect it. However, if there's a relapse in the future and we test, I suspect we would find a 17P deletion. What is the future for 17P testing in myeloma? And I think the other new definition in high risk will not only include 17P loss, but also mutations. So what that means is, and this is unfortunately not being done right now, but 17P loss you can determine by FISH and cytogenetics. But mutations, you need to do next-gen sequencing. That's not going to pop up on a regular FISH report. So stay tuned for that because we think that we're really scratching the surface for all of this.