The paper, published today (19 January 2022) in Nature, suggests that these mutations will cause blood cells to multiply at different rates in different people, and those in whom these mutations cause faster growth have cancer symptoms appearing earlier. If these mutations proliferate slowly, it is possible that the cancer symptoms would never appear, or be noticed after death by other causes.
In the future, it might be possible to detect cancer warning signs earlier, potentially giving the opportunity to prevent or slow future cancer development.
The researchers were able to trace the ancestry of different blood cells and estimate the time at which each patient acquired JAK2V617F and other important mutations. They determined that, in these 12 patients, the first cancer-linked mutations emerged as early as a few weeks after conception and up to age 12, despite cancer symptoms presenting decades later in life.
It is indeed possible to have more than one driver mutation, but this is rare. Many docs do not check for it once JAK2 is diagnosed. (Source - Dr. Jerry Spivak)
I think that one of the issues related to driver mutation proliferation or disease progression is the presence on non-driver mutations. I also suspect that exposure to mutagens/carcinogens plays a role. It also seems pretty clear that high levels of systemic inflammation also play a role. The many complex and integrating factors does make it hard to fully understand.
Regarding the gene sequencing, it can indeed be done with bloodwork. That is how my MPN Myeloid Panel was done. I used this panel.
That sounds like a reference to the JAK2 mutation being homozygous (on both sides of the gene pair) rather than heterozygous (one side of the gene pair). There is some evidence that homozygous JAK2 tends to be more common with PV while heterozygous JAK2 tends to be more common with ET. Note this is a tendency.
The panel includes allele burden. I believe BMB may be more accurate in that regard. They did in fact detect both the JAK2 andNF1 mutations when I had this panel done using blood work.
I have never had a BMB. My docs did not think it was needed. The MPN Specialists recommend not doing one until there is evidence of disease progression in my case. I have not one done in 30 years with MPN. I do not see any point to it unless there is a reason to do so.
I was reading my results for PV exon 12 mutation (one of many) that showed blood allele burden of 5% and a later bmb allele burden of 35.3%. Is this in error or could this really occur? I guess I should ask my doctor.
Samples analyzed by same lab two weeks apart for same mutation. Bone marrow sample on aspirate. In fact, the report suggests it changed saying "gain of function mutation in exon 12 of the JAK2 gene is now at 35.3 variant allelic frequency compared to 5% in previous NGS study...performed on a peripheral blood sample." No further explanation. Didnt think about this until writing this but, at the time of the blood sample on 12/18, I had 8 phlebotomies in the previous 2 weeks and it may have skewed results (like it does alot of blood measures). I think the real number is the bone marrow 35.3%. Wouldn't think 5% could produce the hematocrit of 67% that they found at the beginning (not that I know this sort of thing).
<<The sensitive JAK2B test should always be performed first, as the JAK2 mutation burden may be very low in some specimens. If the JAK2B test is negative, then this assay should be performed for detection of non-V617F JAK2 mutations.>>
JAK2B is their standard test to find the more common type of Jak2v617F. This report is for their special JAKXB blood test for <<JAK2 Exon 12 and Other Non-V617F Mutation Detection, Blood>>
Nothing definitive here but clearly Exon 12 introduces unusual things that may introduce strange results if not carefully provisioned and possibly especially when marrow and blood are compared. One question is whether they did any special exon12 test in your blood draw or instead relied on the standard v167F test..
Agree on the HCT effects. Such a low burden should not cause that much trouble.
In this reference discussed in prior posts less than 10% allele has significance:
<<To explore predictive baseline factors in patients who achieved a JAK2V617F allele burden <10% after 5 years’ ropeginterferon alfa-2b (BESREMi®) therapy and to distinguish this population from patients with allele burden ≥10% regarding clinical outcome parameter>>
I agree your 35.5% does seem more consistent with HCT and other effects. You have good reason to ask you Dr questions.
One would want to rule out a lab error. Yes it can happen that allele burden will increase by that much however. In what time frame was this increase? Was there an incremental increase over time? It is certainly a good question to run by a MPN Specialist.
You've been learning these things way longer than most any of us.
One possible reason to have BMB could be to track any histological changes with INF therapy (recent posts here have discussed) . But as you say, if nothing is actionable, the absence of progression is actually the end point of interest.
I can't find the reference I saw the 4% difference between the allele measurements. It may have been a recent video, one reason I prefer text info. I will try to find. So only my numbers fit that pattern so far.
It has mostly been 22 years of ET - ignoring things other than taking daily aspirin. Followed by 8 years of PV but not knowing the MPN had progressed until 5 years after the fact. It was may very poor experience with a surgery that triggered reactive thrombocytosis that lead ultimately to learning I had progressed to PV. My negative experience with that surgery coupled with learning the MPN had progressed with my old hematologist missing it that made me realize I had to get more educated about MPNs. It was just in time for dealing with the arrhythmia/heart surgery and tumor/brain surgery. Some lessons we learn the hard way, but learn them we must.
I actually agree with the current thinking that it generally does make sense to do an initial BMB. The BMB can then establish a baseline to compare when there is a change in disease status. All of my docs agree that at this point there is no value to doing a BMB for me. Not until there is a change in my MPN Status. If that happens, I will in fact opt for a BMB to see what is going on.
I have seen the same information you have about blood work and BMBs. BMBs do give you more information as well. It is important to compare apples to apples in looking at the results. I am comfortable relying solely on blood work since that is all I have ever done. I will certainly do a BMB when there is a reason to do so.
Agree also on the current thinking to get all the data that is reasonably possible at Dx. With progress lately more of this info could be actionable, or at least good to know.
30 years ago is another thing, since there was so much less info to be had or even know what to do with.
Glad you remember the blood vs BMB allele, I'm not just imagining it. Agree though that comparing the same is more important. I guess I have both options to start.
Thank you so much. I watched an online MPN forum I think during Covid. One of the speakers talked on this very subject. It was really interesting. What you’ve posted will allow me to print off the info. Fancinating isn’t it. So glad I didn’t know about it earlier. Paying a premium for insurance is a nightmare and that’s if you can get it.Imagine being rejected for mortgage insurance 🥴.
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