Genetics and MPNs: Understanding the Basics

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Topics include: Treatments , Understanding and Patient Stories

Should you have a genetic test? Myeloproliferative neoplasm (MPN) experts, Dr. Alison Moliterno and Dr. Stephen Oh, explain how genetic tests can shed light on the pathway of your mutation and why this knowledge is beneficial to your care and course of treatment. The panel also discusses what causes these mutations, driver mutations related to MPNs, such as JAK2v617F, calreticulin (CALR), MPL and whether MPNs are hereditary.

The Living Well series is a Patient Empowerment Network program produced by Patient Power. We thank Incyte Corporation for their support.

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Transcript

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you. 

Andrew Schorr:

Dr. Oh, let’s start this way. People think genetics. I know genetics maybe had something to do with being bald, and I see you have a similar hairline or dark hair or brown eyes or whatever. Hereditary genes; are we talking about that, or are we talking about something different?

Dr. Oh: 

That’s a basic question that comes up with almost every new patient that I see.

The short answer is that when we’re talking about genetics with relation to the MPNs, we’re not talking about those kind of things that you’re born with that may affect your hairline and whatnot. These are genetic mutations that are acquired over time that you’re not born with. They’re not passed down to your children or your relatives, etc. So that is a very important distinction that I try to make clear with every new patient that I see.

Andrew Schorr:

Okay, and one follow-up question to you. People say okay, doc, what gave me this genetic injury, if you will, to lead to these illnesses? Do we know?

Dr. Oh: 

That’s another question I cover with almost every new patient, that I think for that one I guess the answer is a little less satisfying. My answer is that for the most part it’s random chance. 

What I mean by that is that we know particularly from research that’s come out in the last five or so years that all of us acquire mutations randomly over time as we age. But fortunately for most individuals, those mutations land in spots where they really have little to no consequence. But for those that, for instance, acquire the JAK2 V617F mutation or acquire a calreticulin mutation, that really becomes most likely the main driver for what ultimately becomes an MPN.

Patients of course ask did I do something wrong, was I exposed to something? And while we can’t necessarily exclude that those are factors, I think for the most part it’s that just kind of randomly these mutations landed in the wrong place. 

Andrew Schorr:

Dr. Moliterno, we’ve mentioned a couple of these onco genes I think you call them—cancer genes, the JAK2 gene and calreticulin type 2, I didn’teven know about that. 

Can you first of all rattle off some of them just so we know the landscape of what are genes that seem to be associated with MPNs today, knowing that this will probably expand? 

Dr. Moliterno:   

I always like to tell patients a little bit about the history when these were first diagnosed because we talk about them now as if they’re common knowledge, but they are really quite recent in our understanding. We’ve known about the myeloproliferative diseases for more than 100 years, but it wasn’t until 2005 until the driver of many of the diseases was understood to be JAK2V617F. So that discovery occurred in 2005. Before the JAK2 discovery, we didn’t understand really if it was acquired mutations and what genes were involved. JAK2 is the most common of these. 

If you look at 100 patients with the classical MPN, meaning PD, ET and myelofibrosis, 75 percent overall of those individuals will have the JAK2 V617F mutation. Not long after the JAK2 V617F mutation there was a discovery in mutations in M-P-L or MPL. That accounts for about 5 percent of those 100 individuals with either ET or myelofibrosis and then in 2013, that was the discovery of the calreticulin mutations that comprise about 20 percent of individuals who have ET or myelofibrosis. So 2013, that’s fairly recent, and those are the three drivers.

I like to say that if you could put the same mutation, the JAK2 V617F or cal or MPL mutations that we see in our patients, if you could put those, say, in a mouse—they would drive a similar disease in the mouse so that you get polycythemia vera in a mouse if you make the mouse have the V617F mutation. That’s how we’ve kind of come to understand that they drive the disease. They may not drive all aspects of it but they drive the basic process. 

Andrew Schorr:

I know there’s another gene that people have seen too, ASXL1. What is that one?

Dr. Moliterno:   

In addition to these drivers we’ve also discovered a lot of genes that seem to modify the MPN or associate with certain subtypes of MPN. So for instance I said usually JAK2, MPL or CALR can all drive platelet count high and give a disease like ET. Then what happens when patients develop myelofibrosis? We find that perhapsother lesions are acquired. 

Those are genes that don’t drive myeloproliferation so much but they seem to drive the way that the chromatin or the nucleus is managed; they seem to maybe set up the other aspects of MPN that associate with myelofibrosis. And ASXL1 is probably the most common additional genetic lesion or acquired mutation that occurs in individuals with myelofibrosis.

Andrew Schorr:

Okay. Dr. Oh, people may be tested and we’re going to talk about who should be tested and when. How do you know what’s the driver gene? And it sounds like this continuation of identifying genes just keeps going, too.

Dr. Oh: 

Certainly Dr. Moliterno gave a nice circle overview of when the three primary drivermutations were discovered.

We’re sort of lucky now that in today’s day and age we kind of look at this now as standard testing. So JAK2, MPL and calreticulin so much so that many physicians including myself, we kind of go about this in an algorithmic fashion. So for instance if I have a patient with newly diagnosed myelofibrosis, I’ll start by screening for the JAK2 mutation; if that’s negative, go to calreticulin and if that’s negative go to MPL.

And so with those three genes, the majority of patients with any of the three main MPN subtypes, whether that’s QV, ET or myelofibrosis; they’ll be positive for one of those three. There’s a subset that’s at least on the order of 10 to 15 percent of patients with ET and myelofibrosis who will be negative for all three of those mutations, what we’re now calling the triple-negative category. But the vast majority of MPN patients will have one of these three mutations,which we consider the main driver of mutations. 

So in some sense again we’re sort of fortunate that it’s become almost straightforward in terms of at least the top-level genetic testing for these diseases. 

Andrew Schorr:

So that was my question to you, Dr. Moliterno. Some people have maybe had fights with their insurance company or their doctor as related to testing. How do you view this now, and how could it be positioned on how it’s really not elected, if you will, but essential to get a clear picture of an individual patient’s situation?

Dr. Moliterno:   

This comes up in my practice, and I’m sure Dr. Oh’s practice all the time, in that in the olden days before our understanding of what causes these diseases, and again the cause was these acquired mutations and in the olden days we would use histology, looking under the microscope, looking at blood counts and sort of put a name tothis polycythemia vera and myelofibrosis. 

But within that was such a vast variability of what the disease actually was, that that name really did not tell us too much. Now, we’ve really come to understand that what you have is defined by these molecular lesions. They’re not just of academic interest. They actually really tell us quite a bit about what you’ve got, what your prognosis is, and where it’s going. So physicians, we really can’t function and counsel patients appropriately without this knowledge. So there’s no longer elective or of interest. It’s really critical in defining what you’ve got.

Andrew Schorr:

Okay, everybody. You heard it, so this is what you’re advocating for with your MPN specialists, which hopefully you have like the two with us. This is standard operating procedure. There shouldn’t be any question withan insurance company or anybody to help you and your doctor know what you’re dealing with.  

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you. 

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Page last updated on August 29, 2017