All About Genetic Testing in MDS

What is the purpose of genetic testing?

First and foremost, we use genetic testing. to help risks stratify our patients. When we identify a mutation, though in a specific gene, it can sometimes be a marker of whether or not there is sort of detectable presence of MDS. And then we can also look for additional mutations occurring in genes, which may suggest that a patient's MDS is progressing or worsening.

What types of genetic testing are commonly done for someone with MDS?

there are basically two large categories of genetic test. So all MDS patients undergo bone marrow biopsy. That's how you get diagnosed. And with their bone marrow biopsy sample, we test for, genetic, characteristics. So one is to look for any changes in chromosome that's called, cytogenetics study. So, patients may be aware that that DNA is, is packed together in something called chromosomes. So we look for any changes in that chromosome. after that we go further, into the smaller scale where we look for any changes in the DNA itself. That's called, molecular profile or molecular study. So those two cells, genetics and molecular studies are the basic, two basic, studies that that all patients should have when you, when, when they're diagnosed with MDS.

There's really three main genetic tests that are critical. One is cytogenetics or karyotyping. This is really looking at the chromosomes within the MDS cells. Are they are they rearranged differently than the normal, cells. So that's one. Another thing that you can do is called FISH. Or fluorescence in situ hybridization. And this uses specific molecular probes to identify specific MDS related chromosomal changes such as Del(5q) deletion 7, del 20q, +8(trisomy 8). Those are the most common. And then of course, instrument all and over the last two decades importantly is next generation sequencing. So instead of looking at the chromosomes, you're now looking at the mutations occurring within MDS related genes. And so or myeloid malignancy related genes. And you can identify point mutations, insertions, deletions or even loss or gain of chromosomes. And then lastly not used very often in MDS. In the MDS setting, is polymerase chain reaction or PCR based. Assays to assess a molecular alteration.

How often do you need to get a bone marrow biopsy?

So it really depends for a patient with lower risk MDS whose counts are very stable, they may be able to go years without needing to have a repeat bone marrow biopsy. For a patient who is undergoing active treatment for their MDS, we'd usually be checking in with a bone marrow biopsy after a few months, 4 to 6 months, generally on therapy. And so for those patients, we may be doing bone marrow biopsies more often.

How often do you need to get genetic testing?

Every time we do a bone marrow biopsy, we tend to send this genetic testing usually if for a patient with MDS, if we are repeating a bone marrow biopsy, it's because we are concerned about the disease progressing or worsening. And so at that time we do find it helpful to look to see if there are new gene mutations that may reinforce the theory that, a patient's disease is worsening.

Can your MDS genetics change over time? How does this impact the frequency of testing and treatment options?

So MDS genetics can definitely change over time. And again this is what we talked about this sort of thought of clonal evolution, meaning that as the disease sort of worsens or progresses, that new mutations can develop that maybe are driving that progression. So certainly the genetics can change over time. And if we see those changes, you know, if this is, for example, a patient who has lower risk disease, who we've just been monitoring, that might be, you know, the impetus to kind of refer that patient for a bone marrow transplant, if we're concerned that their diseases are falling to a more aggressive type of process.

When is genetic testing done?

as I mentioned before, you always have to get genetic tested, genetic mutations tested in the beginning when you are first diagnosed. That way, you can, get the best therapy. You can get some, idea in terms of prognosis. And then second important, time point where you have to get tested is where, your therapy no longer works or where your MDS relapses. So if you achieve remission, if that comes back, that's the time point where another test is very important because, the clonal evolution that we mentioned, that can happen over time. So your genetic mutations are not static. They can they can change when you relapse or when you when your chemotherapy no longer works. That's actually where you suspect genetic changes. Because the reason that you are relapsing the reason that chemotherapy no longer works might be because the cells are different in terms of genetic profile. So that's another time point where you it's very important to have genetic mutation tested.

Another time point where we test genetic mutations not all the time, but a lot of times is where, where we think you achieved a remission. So at the end of, first set of chemotherapy. So about a month or two later, we test your bone marrow again to see if chemotherapy worked or not. And if you achieve remission, sometimes the genetic mutations disappear. So that's also an important information because when that genetic mutations completely disappear, that can also, portend good prognosis. So that's another time point where we often test for genetic, genetic changes.

What is next generation sequencing?

So next generation sequencing is the current technique that we're using when we do most genetic or genomic testing in MDS, we're able to rapidly look at a very large number of genes, in a rather quick fashion. So it's usually a panel of genes that we're kind of looking to see if there are any mutations and maybe a hundred or more genes, all basically with the same test, using the same vial of bone marrow aspirate or blood. so basically there's a lot of different methods that we use to look at the genetics of a patient. And so, you know, we started with, some fairly basic methods of detecting mutations, and next generation sequencing. You know, to say it sort of simplistically is just a more technologically advanced way of looking at multiple mutations at at the same time. And so what it allows us to do is rather than, you know, looking at, a single mutation, look at, you know, a targeted panel or, you know, even potentially, you know, all the mutations, in a particular patient, at the same time and get that information to help us predict prognosis and treatment. So it really just is, a more sophisticated way of detecting molecular changes. in a cancer patient.

In which laboratory or facility is NGS carried out?

next generation sequencing or NGS, it can, you know, happen through a variety of ways, you know, and we have there's a lot of companies that basically perform NGS for sites, community or academic. So, you know, they are pushing the boundaries of what we can do with molecular sequencing in patients. You know, whether it's, you know, rapid NGS. So, you know, trying to get the information as quickly as possible in a matter of days or, you know, broad based next generation sequencing where, you know, we're not just looking at 40 genes, but we're looking at, like I said, you know, all the genes that could potentially make up a cancer. And then figuring out, okay, what are the ones that are of interest now in what could be potentially of interest later But yeah, so most, you know, some hospitals, some academic hospitals, you know, have their own, ability to do next generation sequencing in house. And so they have a pathology team that then performs those for their MDS or AML patients.

But I would say the majority of patients get their sequencing through a, a third party company. And so, you know, you get a bone marrow or on a blood sample, we send it off to a company that then sequence the blood and sends the information back to us to be then be able to use for these prognostic and therapeutic decisions. you know, in general, for a an MDS patient, we're thinking about two weeks is what we kind of expect for it to take to get the molecular information that we need. But, you know, in my mind, and I think in a lot of, you know, physicians mind is, you know, can in certain patients, can we do it quicker. So I think a lot of the companies are invested in. Okay, let's try to do it in seven days or ten days or even can we, you know, do sequencing in 1 to 2 days. And I think if, you know, we have a specific, amount of genes that we're looking at, that's something that's pretty feasible to do it rapidly. But if we're looking at, you know, everything, you know, you know, we're probably talking in more of a, you know, a 14 day range currently, in what we have.

But but yeah, you know, if there is, you know, what we consider therapeutic implications, for certain sequencing, sometimes we will get a large genetic panel, and then we will get, you know, a targeted panel that, you know, comes back quicker so that we can have the information we need to make those decisions earlier.