Genetic Mutations and Cytogenetics Explained: What Patients Need to Know

What are genetic mutations?

So to explain in a more in an easier to understand manner.

So all cancer including MDS is caused by changes in DNA. So DNA makeups, the part of how your organs are formed, tissues and forms, and this DNA is replicated, whenever new cells are made.

So when there's a mistake in the replication, there is a mutation. And that mutation is called genetic mutation.

So when that genetic mutation happens, the cell that contains that genetic mutation or DNA change undergoes a malignant transformation. So they gain, an advantage to grow compared to other neighboring cells.

So they grow more, aggressively faster, and they form a tumor. That's how you get a cancer.

So if that happens, that mutation in DNA happens in the lung cells, then you get a lung cancer. If that happens in a blood cell, then then you get a blood cancer, something like MDS, lymphoma, leukemia.

Genetic mutations, are, changes to the DNA sequence within cells.

There are mainly two forms of genetic mutations. One acquired somatic, mutations that are not inherited. Then there are also inherited mutations or germline mutations that kind of occur.

Overwhelmingly, the majority of mutations that occur at MDS are somatic, acquired mutations.

They come in a range of magnitudes. Essentially, you can have a very small, base substitution in a gene that then changes the, result in a point mutation in a protein.

Or you can have these great big chromosomal changes that occur in MDS patients.

And so these mutations, these genetic alterations, affect blood cell production. They can give us information about prognosis for a patient's potential treatment for patients.

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What is cytogenetics?

So cytogenetics look at the chromosomal structure generally in the bone marrow cells.

And so before we had, mutations that we would look for in individual genes, cytogenetics were really the only sort of marker or one of the markers that we use to risk stratify MDS.

So, you know, each one of us basically should have, you know, 46 pairs of identical chromosomes or matched chromosomes.

But in MDS patients and in patients with other bone marrow malignancies, pieces of these chromosomes may be rearranged or may be missing.

And depending on what we see in terms of chromosomal rearrangements or deletions or sometimes additions, that can also help us to determine prognosis in a patient who has MDS.

I talked a lot about mutations in the blood. And so there's these, there's the genetic changes that occur that then drive MDS, other cancer types, in addition to that, you know, another main player is chromosomes.

So, you know, if you think about a disorder like, you know, down syndrome, down syndrome is a chromosomal driven disorder where patients have three of the 21 chromosome.

What happens in blood cancers is in the blood itself, not in all of the chromosomes. But in the chromosomes in the blood itself.

There is either a loss or gain that can occur. And, you know, sometimes it's multiple losses even.

But these chromosomal changes that occur, drive, you know, better risk sometimes or worse risk.

And cytogenetics, or what we also called karyotyping, is basically the way that we look at a patient's chromosomal makeup, to be able to get the information that we need to then make therapeutic and prognostic decisions.

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Why is it important for someone with MDS to understand their genetic abnormalities?

It can help us can help to influence prognosis or obviously tell us a lot about prognosis.

Also occasionally when we're doing this testing, we may pick up a genetic mutation that we actually do think was inherited and which may have a risk, associated with it in terms of prediction for other cancers.

So sometimes that mutation may need to be looked at more closely. And family members of that individual may even need to be tested.

We have a couple of mutations that we have targeted therapy for. So that's one way it can determine, the therapy.

Second way is, if a patient has a very, a mutation that's known to cause very poor prognosis, then we somewhat know that they may not respond to chemotherapy as well as someone who does not have that mutation.

So in that patient, rather than trying out our traditional, approved chemotherapy, we may push to enroll them in clinical trials, because oftentimes clinical trials can be better than, more established chemotherapy, especially if we already know, that a patient will not respond to chemotherapy.

Another way would be if someone has, very aggressive MDS with a mutation that we know can cause aggressive MDS, then that we may choose to treat that patient earlier. In a more aggressive manner.

Whereas if you don't have that mutation, then we may sometimes even just watch without any treatment.

A lot of MDS patients may not need any therapy for a while, because MDS can stay dormant for a long time. So a lot of patients, just get watched.

But if you have a particular mutation that we know will not do well over time, then that we may choose to give therapy earlier.

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Is it important to know every genetic mutation a patient has? Is that relevant to their treatment?

Definitely yes, in my stand point.

Even though that there is not huge therapeutic, or targetable mutations in MDS currently, the prognosis, and our understanding of the prognosis based on molecular mutation is there.

And so really getting those tests, you know, much better help predict what patients are going to do well, what patients maybe are not going to do well.

You know, and I think there's certain molecular subsets where, you know, if we know that they're not going to do well, we're really thinking, okay, you might need a clinical trial.

You know, one of those is TP53 mutant MDS. And so that's a molecular subset that we really kind of know, you know, is probably, you know, they might respond to therapy, but the response is not going to be sustained.

And so we're trying to look okay in TP53 mutant MDS, we know we're not going to be able to get a sustained response. Can we do better?

And so that's where we're directing patients to clinical trials using new agents, to be able to target that.

You know, another example would be, you know, ASXL1 mutations. So ASXL1 is another, you know, adverse risk mutation in myelodysplastic syndrome.

And what we know is that, you know, if we are if it is a higher risk patient and we're trying to use what would be the considered the standard of care therapy, which would be a hypormethylating agent.

We know the response rate in those patients is extremely low.

You know, we're talking you know, depending on which study you're looking at, somewhere between 0% and probably at the highest end, maybe 30%.

So another subset where we need to do better.

And, you know, I think, you know, that's with clinical trials, whether it's with, you know, venetoclax, which is an oral BCL-2 inhibitor or other novel agents.

You know, we're able to potentially improve the response rate and prove our ability to potentially get patients to, you know, bone marrow transplants, which is the only way that you can cure myelodysplastic syndrome.

And so genetics are extremely important.

And like I said, the IPSS-M is driven by genetics.

And, and so, you know, without that information, I don't think you can really confidently in accurately, feel like you're making the best therapeutic decision and really telling the patient, you know, all the information they need to know about their prognosis.

So there are lots of genetic mutations that will not affect what we do clinically, and that we may not know the full meaning of that mutation in terms of its effect on a patient's prognosis.

So, in short, the answer is no.

However, as we're, you know, learning more and more and making more advances, it is possible that a gene that's not relevant today may be relevant down the road.