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How Does the TP53 Mutation Impact Prognosis in Myeloma?

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Published on February 6, 2020

Key Takeaways

  • The TP53 gene is responsible for DNA repair and is located on chromosome 17p.
  • FISH tests target the TP53 gene to look for 17p deletion in myeloma patients.

A panel of myeloma experts including Dr. Pei Lin and Dr. Krina Patel from MD Anderson Cancer Center and Dr. Sagar Lonial from Winship Cancer Institute explain the relationship between the TP53 gene and 17p deletion, and what they indicate about disease risk in multiple myeloma patients. Watch now to hear their expert perspectives.

This town hall meeting is sponsored by Janssen Biotech, Inc. and Karyopharm Therapeutics with additional support to our partner, Myeloma Crowd (MCR), from Takeda Oncology and Foundation Medicine. These organizations have no editorial control, and Patient Power is solely responsible for the content. It is produced by Patient Power in partnership with The University of Texas MD Anderson Cancer Center.

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Transcript | How Does the TP53 Mutation Impact Prognosis in Myeloma?

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

Jack Aiello:                

So, can you say a little bit more about that p53 thing? I hear about deletion 17. I hear about deletion 17p. I hear about p53. How are they related?

Dr. Lin:

The gene is called a TP53. It’s located on chromosome 17p. So, we can look at it in different ways. One way is to look at the chromosomes, like as I show here. So, I look at chromosomes. Sometimes, that is not sensitive enough. So, you also do FISH, which specifically targets that particular gene. 

So, the issue with FISH is that it’s more sensitive, but it only looks at the particular gene. If we look at the whole chromosome, the karyotype, we can tell more than just the p53 deletion, but the other adverse factors, such as 4;14 translocations, so on and so forth.

So, there are also many other ways we can contribute as pathologists. So, we can look for the biomarkers from the immuno-histochemistry, like looking for p53 expressions at the protein level. So, when there’s a mutational deletion, there tends to be expression of that particular protein.

Also, we can look at the gene expression profiling as well as the next generation sequencing to see if there’s any mutation. If you have mutation and deletion of p53, that tends to be more aggressive than just a single isolated deletion or mutation.

Dr. Lonial:                 

So, I think that’s a really important point, the idea that p53 is a gene which is responsible for DNA repair. It’s located on 17p. For the trivia night that you guys go to, the p in 17p stands for petite because it’s the short arm and the long arm is q because q is after p. That’s actually where that came from.

Dr. Lin:                      

Right. 

Dr. Lonial:                 

You can have missing portions of 17 where you don’t have a copy of p53, but you’ve still got one functional copy of p53 because you have two copies of every gene. If you have a mutation, that’s a much bigger deal, because you may or may not have a normal copy if one is missing and the other is mutated. That’s a subset that we know early on does not respond nicely to therapy or if they respond, they don’t stay in remission for very long. 

Jack Aiello:                

So, if a doctor tells me you’re a high risk because you have deletion 17p, does that mean all my myeloma cells have this deleted chromosome? Does that mean a certain percentage do?

Dr. Lin:                      

That’s a very good question. When we do FISH, we can actually quantify how many cells because we normally will study 200, sometimes even 500 cells to see what percentage of cells actually have the deletion.

Depending on the clinical data using different kinds of testing assays, some use the 50 percent cutoff, others use lower cutoff. I’ll ask Dr. Patel and Dr. Lonial to answer that question. But the idea is that the higher the percentage, the more aggressive it’s likely that the tumor may not respond to therapy. So, that’s a very good question.

Jack Aiello:                

Do you all, Dr. Patel, use a standard cutoff?

Dr. Patel:                    

So, we use basically anything that’s positive per our FISH assays we consider positive. However, the more cells that have 17p, I keep a closer eye on it. The French data shows that if you have 60 percent, that’s really where it’s positive, but we also have data that even if it’s lower—and everybody has their own sort of positive, so, it’s hard to compare all these trials. 

But for me, if it hits positive and my pathologist is telling me it’s positive, then it’s not just a false negative, then I consider that as positive. 

Jack Aiello:                

So, positive could be 1 percent of the cells, yes, no? 

Dr. Lin:                      

That’s a very good question. The way we do the test, in many places, we enrich the sample, meaning we only test the samples that have been selected over plasma cells. So, then we can tell you exactly what percentage of plasma cells instead of percentage of all the cells that we have to look at that has the deletion. It’s a very important question to answer to ask. 

So, that’s why sometimes when you read the pathology report, it’s very complicated. It can be quite intimidating because you have to look at what you’re reading. I have a friend whose wife was diagnosed with myeloma and in the beginning, she was told that you have only two years of survival because you have this deletion. It turns out it was not exactly the case. The family was very devastated. 

So, even for sometimes physicians, it can be quite intimidating, let alone for the patients sometimes to read these complicated reports. The question here you asked is very important – what percentage of the tumor cells actually have the deletion? That is the key question.

Dr. Lonial:                 

I think the 60 percent cutoff is what you need if your readout is a short-term readout, meaning within three years, to see whether there’s a difference. At least in our view, 17p is sort of like being pregnant. Either you have it or you don’t. If you have it but it’s at 20 percent or 30 percent, it’s still there.

With subsequent relapses, it’s going to get enriched in higher numbers. So, it’s somebody that we’re much more aggressive with in our early therapy to try and prevent the sort of emergence of drug resistance than somebody who doesn’t have it at all.

Jack Aiello:                

That might also explain why at diagnosis, maybe nobody mentions anything about 17p, but at relapse, someone says all of a sudden you’re 17p, a small percentage was there initially. Unfortunately, as the clone changes, that percentage has increased.

Dr. Lin:                      

That’s a very good point. 

Dr. Lonial:                 

Or you acquired it. We know that, as you said, myeloma cells get smarter as they are around longer. If you are a cell, one of the things you’d want to do is get rid of p53, because it allows you to genetically do whatever you want. So, as a cell evolves, it may lose one copy of 17p as part of that evolution.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

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