BETA - What is p53?

What is p53? So p53, tumor protein p53, is one of the main tumor suppressor proteins. It's been actually called the guardian of the genome. And its mutation or alteration is a bad prognostic sign in really all sorts of cancers. It is a protein that is primarily responsible for maintaining the integrity of one's genome, and so it directly binds to DNA. And when it becomes dysfunctional through mutation or simple removal, then it makes one more prone to cancers overall. The gene that encodes for p53, TP53 gene, is found on the short arm of chromosome 17, that's 17p. And so when a given patient is said to have lost 17p in their given cancer, myeloma in this case, that means that they do not have a functional p53 working against those cancer cells, and hence that is considered a high risk feature. And again, that's a high risk feature for numerous cancers. So when we do the bone marrow biopsy at this point, since we don't have the option of doing a liquid biopsy yet, we always do karyotyping and FISH testing. And then we can also do molecular testing. Molecular testing can tell us if we have mutation of the p53 gene, and it can also tell us if it's one allele, or heterozygous, or if both alleles are missing in the cells that were analyzed from that sample. The FISH will help us tell if there's a 17p deletion, but the molecular testing or the gene expression profiling are better at telling us whether the p53 gene is mutated or absent in the myeloma cells. So typically we look for p53 alterations by cytogenetics in FISH. We look at whether or not the actual chromosome is altered, and if we see the short arm of chromosome 17 as being in somehow disarray, that implies TP53 being an issue. We can also, though, as with some other cancers such as leukemias, we can actually direct typing of the gene and look for mutations that way. That is not a standard part of myeloma practice, because it has not been shown to really change the outcomes, but that is something that, as a research question, is actively looked at. Does having a deletion of 17p always correlate with a p53 mutation? Having 17p deletion or deletion of the 17p gene does not mean that you're automatically going to be missing the TP53 gene in that chromosome. The more 17p deletions that we see in the cancer, the more likely you're going to be missing that gene of the TP53 just by logic. The more abnormal or missing portions of that gene you're going to have, the more likely it is that you're going to have less quantity of that p53 gene. But it doesn't necessarily mean that because you have the 17p deletion or the deletion of 17p gene that you're automatically going to have a loss or a mutation of the TP53. It's almost as if you had a talent, maybe it'd be singing or painting or running. You might have it, but you won't know you have it until you actually try singing or painting or running. And nobody else is going to be able to see how you express that talent until you actually do it. So in cancer cells, you might have the deletion of 17p, but it's not necessarily going to translate to the effects of having the loss of the TP53 and having the myeloma cell go out of control and dysregulate it in terms of apoptosis. It just tells you that it does increase the likelihood of missing that gene, but it doesn't necessarily mean that you automatically have lost that gene. For every chromosome, there are two copies of the gene in the natural form that we're concerned about. And the normal state is that you have both copies of the gene, because you have two sets of chromosomes. If you have two copies, you're okay, right? You're what we call wild type for P53. If the whole area of the chromosome containing the P53 is lost, then you have lost one copy. That already creates more conditions where the myeloma can be more aggressive. Losing the second copy and basically creating a situation where the plasma cell completely lacks any functional P53 sets the stage for even more aggressive disease. So it's important to know in each and every patient the status of that area of the genome 17p, and it's important to know the status of the P53 gene.