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Genetics and PV: What Does It All Mean?

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Published on November 11, 2015

With the advent of unlocking genetic code, the cancer community has now been introduced to the concept of immunotherapy. What does this mean specifically for MPN patients? For Dr. Srdan Verstovsek of MD Anderson Cancer Center, genetics hold many answers but add a level of complexity related to prognosis and treatment. Dr. Mark Heaney of Columbia University Cancer Center views genetics in terms of interpreting how aggressive the disease may be, while Bob Rosen, patient advocate and Chairman of MPN Research Foundation, suggests that patients put the role of genetics into perspective by connecting with a specialist.

The Conversation, MPN Edition is a Patient Empowerment Network program produced by Patient Power. We thank Incyte Corporation for their support.


Transcript | Genetics and PV: What Does It All Mean?

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:     

We MPN patients have been hearing about oncogenes—not hereditary genes but oncogenes, things gone haywire being identified.  Certainly the JAK gene that you mentioned, we’ve heard about calreticulin.  There’s another one, is it MPL, I think, if I get it right?  Others, and maybe you guys will find others.  What does that mean, these genetic discoveries, for PV?  Dr. Heaney, do you want to take a shot at that first?

Dr. Heaney:         

Yes.  I think one of the things that was surprising about the discovery of the mutation in the JAK protein was that the same mutation was seen in myelofibrosis as well as polycythemia vera and essential thrombocythemia.  And yet those diseases, while they share some overlapping features, are really clinically distinct. 

So that told us that there were other genetic changes that were likely influencing some of those differences in biology.  Now, I think identifying the change that separates essential thrombocythemia from polycythemia vera has still been a little bit elusive.  And we think that some of the differences may be related to the number of mutations, the penetrants we described of JAK2 mutation or the allele burden in patients with polycythemia vera which tends to be higher than essential thrombocythemia.

But I think that as we understand more what other genes are mutated, we’ll have a better understanding of potential targets for therapy and may also be able to give patients more information about how likely their disease is to progress so that we can maybe relieve some of Bob’s concern that he may be one of the ones that’s more likely to progress. And in that sense, knowledge is power. 

And we believe that some mutations—there’s a gene called ASXL-1—may be associated with more aggressive biology than patients who don’t have that mutation.  So I think we’re still at the very beginning of what I think is going to be a huge boom in genetic information, and it’s going to require a lot of computing power to try to sort everything out.  But it’s a very exciting time.

Andrew Schorr:                  

Dr. Verstovsek, I'm going to have you continue that.

I often feel like I'm going back to biology class, but now in the 21st century.  You all are looking at the biology, but do you know what’s significant yet for PV? 

Dr. Verstovsek: 

You see, first question that usually comes to mind—and everybody comes with that question to MD Anderson is saying, “What did I do wrong?  Did I acquire it?  Is it one problem that caused it?  Can I fix it?  Did I do something wrong?”  And it’s not.  It’s not one cause.  We don’t even know what the cause is.  And it might be different causes, and it’s not something you acquired from the environment.  It is the complexity of the biology with influence from outside that makes for the disease.  So you hear about this JAK mutation, you hear about calreticulin mutation, MPL mutation; you mentioned a few.  But it all comes down to usually that hyperactive pathway inside the cells that is active and makes cells grow, and it’s active for different reasons.

Now, what happens over lifetime of the patient is you have initiating factors.  But then the cells grow, obviously, as we live.  And they may acquire other mutations as they grow.  So it’s like a branching tree.  You have a tree and you have multiple different acquisitions of mutations in different cells, and you may have sub-clones of different cells.  You can have these branches be thicker or thinner and some clones, so the cells take over the others.  This is much more prominent in myelofibrosis than in polycythemia vera.  But there is evidence for this in polycythemia vera, as well.  You would say that PV is simpler, genetically.  But there is evidence that this complexity may, like it was suggested, lead to all patients [doing] worse over time, perhaps, transform sooner, or not even respond very well to therapies.

There are studies—papers that are saying that patients on interferon, if they have more genetically complicated disease with more mutations do not do as well as patients only with the JAK2 mutation where it’s multiple.  So we are learning as we go how to utilize this genetic information in everyday life.  We, unfortunately, have so much genetic information that we don’t many times know what to do with it.  And the laboratory testing isn’t much way ahead of our clinical utility.

And it may be sometimes too complicated to explain it to a patient, because we face such a different genetic testing and results and what to do out of it, because we have only a few medications to use.  So we try to do the best we can, and it’s an ongoing process.  There is nobody to fault about it, and this is how it is.  It’s not black and white.  It’s continuous grey, and it gets lighter and darker. And this is how the life goes on and the life of PV patients and us as the clinicians.

Andrew Schorr:                  

Bob, I want to ask you from the patient’s perspective but also as chairman of an organization helping fund research, moving it along.  We read your newsletters, and you’re making grants, and we hear about gene discoveries and research.  But it’s wonderful, but sometimes it’s crazy-making, too. We don’t know where it’s gonna lead.  So I know you're trying to move it ahead, but what would you say to patients to put maybe this genetic sleuthing in perspective for what it could mean for us? 

Bob Rosen:         

First, I'd like to say, while I have a moment, how grateful the patient community is to the scientists and the clinicians who are so committed to working on the MPNs and all the enormous amounts of progress that we’ve made in recent years.

But I do agree with Serge that the amount of information can be overwhelming, and trying to sort through and determine where to go with what pieces of information is an enormous challenge.  I am very encouraged not just with the work that was discussed today but with all the new mechanisms of action that are appearing in cancer science in general.  I'm talking about immunotherapy. I'm talking about this new—the new technique that is called crisper gene editing.  I'm very interested in what we might be able to accomplish if we could find a very specific JAK inhibitor, one that worked just on the mutation and not on the entire—the wild type as well as the mutated gene.  So I don't know if this answers your question, but I feel there’s a tremendous landscape in front of us, and we keep plugging away 

Andrew Schorr:                  

And I think, again, in discussions with two specialists like this, and I urge people—and I know you do—to connect with a specialist in the MPNs to really help them personalize what’s in the lab, what’s approved, what’s in clinical trials to us.  And then we have, hopefully, an ongoing discussion over many, many years.  As our condition may evolve, the treatments may evolve. 

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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