What do I need to know about TP53 the gene?

Before diving into this lesson, here's a quick genetics refresher.

Humans have 23 pairs of chromosomes, one copy from mom and one from dad. Genes, which are made of DNA, are arranged along these chromosomes, meaning we have two copies of each gene called alleles, one inherited from each parent.

If this sounds a bit confusing, don't worry. You can check out the HealthTree University Basic Genetics and Tumor Biology course for a deeper understanding before continuing.

What is TP53? The gene responsible for making tumor protein 53. And where is this gene located? p53 is a tumor suppressor gene. So we are created with the ability actually to suppress cancer and to suppress malignant transformation.

However, when p53 is one of the most common and when it is mutated, oftentimes cancer develops and is typically associated with a more aggressive course across the board. Multiple myeloma included, other heme malignancy CLL, and so that is thought to be one of the highest risk mutations.

So it's a mutation of a suppressor gene to suppress cancer. We all make little cancers all the time. Our body is supposed to catch it, reject it. And when you have a mutation of p53 gene, then it allows the cancer cells to exist and to replicate and to expand sort of unregulated.

It's a gene that's encoded on the 17th chromosome. So on our chromosomes, we have a long arm and a short arm. And so the 17p is the 17th chromosome and the short arm of the 17th chromosome. And on that is where p53 is sort of encoded. And so that's a gene product of the 17th chromosome.

There are some of these genes that are canonically or classically recognized as being important for cancer. p53 is one. It's a tumor suppressor gene. So its normal function in cells is to make sure that if there are any errors within the cell's replication, the p53 kind of recognizes it and stops those cells from developing or corrects those mistakes.

So it's considered as a master regulator for normal cell. So we all need p53 to make sure that cells do not become cancerous. We have two copies of p53 that for most of us do the job. But if cancer cells are missing one or both of those p53, then that's when cells become cancers.

And interesting anecdotal, elephants do not develop cancer as frequently as humans, even though they're very large. They have more cells than we do. And typically you would expect that because they have more cells, more cells replicating, you would see more cancers. But elephants actually do not develop a lot of cancer interestingly.

And one speculated reason for why that is is because they have not two copies of p53, but often ten, 20, 25 copies of p53. So one theory for why elephants do not develop as much cancer as humans or other animals do is because they have extra copies of p53 that protects them.

So p53 is considered a pretty important. It's not the only gene that's important, but certainly one of the key genes across different cancers, myeloma, other blood cancers, even solid cancers. p53 is an important gene, and its alteration is important in many, many different cancers.

What is the difference between a TP53 deletion and a TP53 mutation? A TP53 deletion removes the gene entirely from one copy of chromosome 17p, meaning the p53 gene is missing. In contrast, a TP53 mutation means the gene is present but has a DNA sequence change that alters the protein, causing it to function improperly.

Why is it important to know the status of the TP53 gene in each allele? That refers to the fact that you are looking at two p53 genes for every cell. Correct. So the normal state is that two genes will be there in their intact form. That's the normal state. That's what we call wild type.

The ways that p53 can be affected are many, not just. So when we talk about deletions, a deletion refers to the whole area of the chromosome just being lost. Essentially, you know, you have a pinching out of that area of the chromosome, taking the p53 gene with it. And that just gets lost. Right. So you are left with one copy.

So when we talk about 17p loss or 17p deletion, we are talking about the physical removal of that whole area of the chromosome that contains the normal gene. So the question is what happens to the other copy. And the other copy can be affected through a number of different mechanisms.

One could be through a mutation that interferes with its function. So the gene is there but it is faulty. There is a change in the sequence of DNA that inactivates the gene. So you have one loss, a completely lost copy, and another copy that is faulty. And that is a situation where you would consider that you have lost pretty much all the useful function of p53. Right?

But of course, the second copy of the gene can be lost in some patients through a process similar to loss of the entire region, as I mentioned before. So you could have both copies that are lost or completely gone or one copy that is lost and another copy that is there physically but in a faulty version. So you really need to know what the status is before you can further ascertain the risk status of the patient.

How is TP53 status determined? How will someone know if the TP53 tumor suppressor gene on each of the two alleles of chromosome 17 is working properly? As of right now, again, it's based on the bone marrow. And so the FISH analysis, the cytogenetic FISH test, is what picks up chromosome abnormality. So that detects the 17p deletion.

The p53 either has to be—it is available by immune staining of the bone marrow biopsy. So the pathologists have a particular stain that will express a certain uptake related to p53. So you're looking more at a DNA level as opposed to a chromosome level. And so you're actually looking at the product of the chromosome, which is the p53.

So there are these DNA sequencing, next generation sequencing studies that are done of the bone marrow as of right now, that looks for the p53 mutation. So FISH 17p is through FISH, and then p53 is through either DNA sequencing of a bone marrow at this point. Although, again, there are new blood studies that are being done looking for that. It's just that multiple myeloma typically is not highly circulating in the peripheral blood. And so that's why the bone marrow still is sort of the standard.

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