Why is del17p in multiple myeloma so aggressive?
Deletion 17p is one of the most aggressive features in multiple myeloma. What makes it so? In a recent interview on Myeloma Crowd Radio, Dr. Robert Orlowski, MD, PhD of the MD Anderson Cancer Center gave an excellent explanation about what happens with the del17p and how having that deletion affects another key gene, p53. According to Dr. Orlowski:
What the deletion of 17p means is that a portion of chromosome 17 on the short arm (which is what the p stands for) is actually deleted. When mapping has been done to try to identify what genes are mutated as a result, the gene that is most commonly found to be lost is the gene called p53. And many of you who are cancer scholars may have heard about p53 before. It’s a very important gene. Some scientists have called it the defender of the genome, if you will.
The p53 gene plays a critical role to protect the genome from malfunctioning.
What it does is when the p53 gene and protein are present and normal, it acts as a proofreader, if you will, so that when your cells divide, they have to make a copy of all the chromosomes which are the instruction manual for the cell about how to do its function. As you can imagine, occasionally some mistakes are made and if those mistakes were not caught, then the genes in which that mistake is made may not function normally. What p53 does is it helps to scan the genome looking for mistakes. If a mistake is found, what p53 does is, in combination with other proteins, it stops the duplication of the chromosomes, it helps to make a correction in the mistake and then it lets the cell resume going ahead with division. So again, it’s kind of like a proofreader. If, for some reason, the mistake cannot be corrected, the next thing that p53 does is it causes the cell to die. And that is helpful because you don’t want cells growing in your body that have mistakes or mutations in the instructions about how they’re supposed to work.
The p53 loss is so common in other cancers that a New York Times bestseller book was recently written about it.
It turns out that p53 is probably one of the most, if not THE most, mutated gene in cancer. The 10% to 15% that I mentioned in newly-diagnosed myeloma is actually one of the low levels. If you look at solid tumors at diagnosis, sometimes 50% or more of patients have a mutation of the p53 gene. It’s actually a gene that we’ve known about for many decades and there have been wonderful scientists in the field that have studied its function. So that’s one reason why you can actually write a whole book just on the p53 gene itself. P53 turns out to be very commonly mutated in many different cancers and the reason for this is that if you think about what the cancer cell wants to do, it wants to grow very quickly. And therefore any gene or protein which slows that down and that’s part of what p53 does, the cancer cell will grow more quickly if p53 is mutated or deleted. Also, cancer cells have what’s called genomic instability which means that they make more mistakes when they copy the chromosomes and some of those mistakes may actually harm the cancer cell causing it to die but other mistakes may give the cancer cell an advantage and allow it to grow more quickly and more aggressively. And if p53 which is the proofreader is mutated or deleted, then there is a greater chance that these mutations will occur. So by mutating or deleting p53, the cancer cell has an advantage in survival as well as in growth and we know that patients with this abnormality in their myeloma cells have a worse outcome than people who have a normal p53.
It is also involved in some viral infections.
Probably the best example is when women develop cervical cancer which often is because of infection with a high-risk Papilloma Virus. What the virus does is it doesn’t mutate p53, it actually has a gene that comes along with the virus that digests p53 inside the cell. And because the levels of the p53 protein are then very low, it’s the same as if a mutation had occurred. And this gives you an example of how important the gene is because even a virus has figured out a way how to get rid of it and that helps the cells to divide more quickly which gives the virus a survival advantage.
There is a critical link between the p53 gene and the way that it affects chemotherapy.
What we know about chemotherapy is that many of the chemotherapy drugs work in part with the help of p53. So if p53 is mutated then many of the chemotherapy drugs that we use don’t work as well against the deletion 17p as they do against normal cells or against cancer cells that have a normal p53. And that’s kind of the crux of the problem. All of the drugs that we currently use — whether we’re talking about bortezomib or carfilzomib or thalidomide, lenalidomide, pomalidomide, cyclophosphamide, doxorubicin — all of these drugs were developed without an understanding of the effect that deletion 17p and the p53 gene have. And so that’s the core, the real focus of our program.
How common is the del17p present in multiple myeloma?
In newly-diagnosed patients, somewhere between 10% and 15% have this deletion of 17p but then as the disease progresses and you get first to the relapsed and then to the refractory setting, the proportion of patients that have this abnormality goes up. Some studies suggest that it can be as high as 30% and a few even suggest that it may be as high as 50% for people in the refractory area. So this really could be a major population of patients with myeloma.To learn about what is being done to overcome this genetic problem, listen to the show.