Study shows more Driver Mutations in General Population

[EPguy]

The Denmark study used super sensitive tests.. MPNs may be far more common than current info suggets.

The image here shows 3% have a Jak2 mutation even as most of these have no MPN Dx.

Their cutoff of 1% (orange circle) still includes way more than MPN with Dx (grey circle)

Highlights:

Their point is all these are at risk of high bloods and MPN.

The authors suggest even very low alleles may retain risk.

They also say CALR is more likely to turn into MPN.

--

ashpublications.org/blood/a...

Survey of 19,958 adults:

<<In a population-based screening of 19 958 adult citizens by highly sensitive ddPCR, we found a novel CALR population prevalence of 0.16% with mean allele burden of 7.5% and a JAK2 V617F population prevalence of 3.1% with a mean allele burden of 2.1%.>>

So Jak2 mutations are in ~3% of everybody. Bad habits added to the risk of having a mutation.

CALR is more likely to turn into MPN:

<<suggests that a higher percentage of the CALR positives in the general population evolves into MPN compared with JAK2 V617F positives>>

With any Jak2 mutations risk to become MPN is high:

<<high hazard ratios of 11 and 12.9 for hematological malignancies in individuals with detectable mutation found in the above-mentioned CHIP studies>>I think CHIP is a sort of pre-or-undetermined MPN. But I think these studies were not as sensitive as the present one so may have not caught the very lowest alleles.

This study found much higher prevalence of Jak2 in the population likely because its high sensitive test:

<<The JAK2 V617F prevalence of 3.1% in our general population study is 3 to 30 times higher than in earlier reports>>

MPN may be much more prevalent than thought:

<<If just half of the 80 high-risk individuals with elevated blood cell counts meeting diagnostic criteria turn out to be true MPN patients, the MPN prevalence in our study population increases 350%.>>

--

MPNs have low cholesterol:

<<The lipid profile with low cholesterol values in almost all mutation-positive subgroups is in accordance with observations from MPN patients>>

This is news to me. I do fit this profile.

Any driver mutation may increase odds of MPN:

<We therefore suggest that individuals with a driver mutation, even at a very low mutant allele burden, are considered MPN-risk patients.>>

Maybe any therapy needs to get get rid of all of it to be fully curative.

[amalekh]

Hi ETGuy,

Very interesting and important study, thanks alot for sharing.

I wonder if JAK2 is the real driver mutation!

Cheers,

Malek.

[charl17]

I have always wondered why and how mutations like JAK2 escape the body's immune system. Why do most people either wipe out these mutations or contain them with no symptoms?

But what I find most interesting in your post is the correlation between low cholesterol and mpn. My cholesterol is borderline low and I have MF.

[EPguy in reply to charl17]

I think it is rare to eliminate the mutations. Even with INF it is usually reduced but not gone.

This study says those with very low alleles and not considered to be MPNs can share some of the MPN complications.

A lot of big claims that would benefit from being reproduced by others.

[cmc_ufl]

Having over a decade of occupational experience with PCR, I have doubt about the results in this study. The difference in the sensitivity of their approach is not far off from what many other groups use, none of which report these values.

There is no way 3% (1 in 33) of the general population has the JAK2 V617F mutation. Most likely, sample contamination at the lab bench is the cause of this finding.

[EPguy in reply to cmc_ufl]

Thanks for the pro input, I know nothing about PCR except we've all heard of it via Covid.

Here is a few lines from their procedures from the supplementary info, see link:

They claim to have confirmed the linearity and LoD. Is there actually anything novel?

Is it possible the procedure has always been capable of this but no one bothered to take it to that level? (That would meet the definition of novel if not creative.)

<<DNA analysis was performed on the QX200 system (BioRad, Hercules, California, USA) according to the manufacturer instructions>>

<<The assay linearity and LoD was confirmed in a fourfold dilution series of DNA from a JAK2. V617F positive sample spiked into a fixed amount of JAK2 wildtype normal donor DNA. Each dilution was analyzed in replicates of eight (Supplemental Figure S3).>>

ash.silverchair-cdn.com/ash...

[Manouche in reply to cmc_ufl]

It says 0.2 % of the general population in some other studies.

[EPguy in reply to Manouche]

Agree, this study is an outlier. That seems to have been their goal, to look in a different way in a large sample size for the alleles, but as cmc_ufl says, this may not valid.

[EPguy in reply to Manouche]

The danish study did have a large sample size, maybe this is relevant. Do you know what the samples were in the prior studies?

[Manouche in reply to EPguy]

« Among 49,488 individuals from the Copenhagen General Population Study, 63 (0.1%) tested positive for the JAK2V617F mutation in the time period 2003–2008« ncbi.nlm.nih.gov/pmc/articl...

[EPguy in reply to Manouche]

Thanks for the reference. I've not looked at this one carefully before. This is the report you refer to on the 2% cutoff for progression, correct? Quite compelling, while the n of actual MPN Dx's is low. << Furthermore, a novel observation was that no individuals with a

myeloproliferative neoplasm were found in cases with an allele burden

below 2%,>>

The chart here from this report is the best display of the 2% limit.

The light pink bar with 4 in it shows none of the under 2% alleles were

later Dx with MPN. But large portions of those above 2% were Dx.

--

My summary on the separate issue of the comparison: The prevalence difference has a rational basis with caveats as below.

Please check if this makes sense.

Both are from Denmark but different authors. The top post study ( I include the % for easy tracking) "Prevalence and phenotypes..(3%)" references this one "somatic mutation...(0.1%) " and authors of "Prevalence and phenotypes.(3%) ." claim the intent was <<by use of a highly sensitive method>> to study mutations. They don't explain how it is improved over "somatic mutation...(0.1%) while "somatic mutation...(0.1%) also claims a highly sensitive assay. But "Prevalence and phenotypes..(3%)" is a newer study and what is considered sensitive may have changed. This is the area of expertise for cmc_ufl who has said here that these sensitivity diffs do not make sense.

--

** Reason for higher % population detection:

The other info I infer from this chart is they used a 0.8% cut-off for allele detection in "somatic mutation..(0.1%) ." since that is the lowest shown in the chart. I can't find a text reference to this, except comparing it to another assay at 2% limit.

In "Prevalence and phenotypes..(3%) ." the cut-off was <<The sensitivity of the assays was calculated to be 0.009% for JAK2 V617F>>

Assuming above there are two orders of magnitude difference in sensitivity and if there were not a large population prevalence difference it would be a surprise.

But as cmc_ufl notes, is the extreme 0.009 limit actually possible?

2% MPN Jak2 Limit

[EPguy in reply to cmc_ufl]

See my notes on comparing the study manouche linked to. As you say, is the claimed 0.009% possible?

[Wyebird]

Thanks, I noted that bad habits might be the trigger to making our MPN more active, I’m an ex smoker. My cholesterol isn’t low. Maybe nearly everyone has a mutation waiting to happen - hence a multitude of illnesses that develop later in life.

[Bluetop]

Thanks for posting -interesting -also cmc_ufl response, to something in a peer reviewed journal -great to have that insight. I agree, the cholesterol is interesting -mine has been 'normal'.

[Annula]

Very informative message. Looking at the study it states 'bad habits add to the risk of developing JAK2 mutation. I would be interested to know what these bad habits are, as I have always tried to lead a healthy lifestyle & diet.

[Lena70 in reply to Annula]

That part bothers me. I’ve always been fit and active, eaten nutritiously, have never smoked and drink in moderation. Is there some bad habit of mine I’m not aware of?

[EPguy in reply to Lena70]

Exposure to unknown chemicals in drinking water is one possibility. There a well known PV hot spot in Pennsylvania , USA.

One of these chemicals gets my attention, Arsenic Trioxide (ATO) This, combined with INF had brilliant results in mice and clinical trials are planned.

These are a witches brew of bad actors.

targetedonc.com/view/advanc...

<<..a probability of this being a random event was less than 1 in 2000>>

<<The chemicals found in the cluster area include arsenic trioxide, benzo(a)pyrene, potassium chloride, ethylbenzene, benzo[k]fluoranthene, styrene, cadmium chloride, hydroquinone, 1-1,1-trichloroethane, TCDD, TCE, methylene chloride, sodium cyanide, and manganese chloride>>

[Lena70 in reply to EPguy]

I was born at Camp Lejeune in North Carolina. We lived on base several years. I was born during year one and we left when I was almost three. The water at Camp Lejeune was tainted by a leak from the dry cleaning facility. Our house was right across the street from the dry cleaners. I first learned of the contaminated water from a news story in 1999, but my father was contacted soon after by officials. When I received my diagnosis, I called the number they gave us in case we developed the illnesses suspected to be attributed to the water. I was told they were no longer following cases . I'll never know if the tainted water in my formula bottles doomed me. My brother has had no major health issues and my dad is ridiculously fit for a 76-year-old. Of course, he was in Vietnam or oversees for most of the time we were at Camp Lejeune. I did find a woman my age who was also born at Camp Lejeune who has an MPN.

Before the MPN, my husband and I used to joke that anything wrong with me was from my drinking dry cleaner fluid. It isn't so funny now.

va.gov/disability/eligibili...

[EPguy in reply to Lena70]

That is a lot of chemicals. I see they use the term "Myelodysplastic syndromes". That includes MPN to by understanding, but is an older less specific way to describe it.

[Solyesh]

Very interesting..on the cholesterol I fit the profile as mine has always been my my GP states "amazing" (meaning very good/low readings) - as for the bad habits also interesting. As I said in another post - I had blood tests for years prior to my diagnosis and can pinpoint exactly when the JAK2 mutation kicked in (or at least when I got my first abnormally high platelet reading which then remained high in every reading until diagnosis).

I can't see that anything changed during that time (perhaps stress level as I was a new father and started a job with increased responsibility in a new city?). As for bad habits, perhaps like any health-related issue, bad habits do not help..but I think many of us most likely also just got the "unlucky draw" as far as mutation developing into MPN. I have tried to be healthy all my life (non-smoker; very occasional drinker; no drugs; lots of exercise; Mediterranean Diet; yoga..so who knows...)

[EPguy in reply to Solyesh]

i have the same info, PLT starts to rise in 2013. Not till 2020, when I was feeling *really* wrong and ready to go to ER, did I get Dx at 1,000 PLT.

[MaggieSylvie]

Well, to me, that would suggest that people are carrying these mutations and they turn into MPNs in later life, which is when they are usually discovered. However, does this knowledge suggest that everyone should be screened? What are the bad habits that take a part in causing a mutation? I don't know if you can answer these questions, but your research is interesting. Thanks.

[EPguy in reply to MaggieSylvie]

The current info points to early acquisition of the mutations, with at least a tendency to get one occurring early as the womb. Hunter has posted on this area.

Bad exposures make MPN trouble more likely, but like the 100 yr old smoker, exposure is not always fate.

Most of us had lead exposures in the leaded gas days, that could add to trouble for everyone from that age.

[MaggieSylvie in reply to EPguy]

Leaded fuel! Forgotten about that.

[Pte82]

ETguy, my wife's ET started from benzene and toluene from a large industrial lab where she worked. All of her co-workers are now dead, one I knew their platelets went over four million did not respond to treatment. It has been known since 1938 these chemicals cause myelofibrosis. The toxic load in Denmark from benzene and toluene as well as others may offer a component to explain the results in the study. This article mentions benzene and bone marrow.

annalsofglobalhealth.org/ar...

[EPguy in reply to Pte82]

Toluene and Benz are top of many lists I've seen for MPN. I had brief toluene exposures early on with auto repairs. Gasoline has/had benzene. I believe it is still in of stuff paints solvents etc.

That is quite interesting re Denmark. Is there documentation of that hazard there?

[MWxxxx]

Oh, and there was me thinking that my brilliant chorestorol levels were a real positive and might save me from having an mpn blood clot episode! Now it seems it may actually be a symptom of my mpn. I wonder then if my chorestorol level is accurate or if it is the mpn masking or making it look better than it is. I've always thought I must be very lucky to have such good levels (low on the bad chorestorol and high on the good) as I eat far too many cakes and biscuits. Maybe I should cut back just in case.

[Mostew in reply to MWxxxx]

Sweet things are inflammatory , not good for us not just because of cholesterol..

[MWxxxx in reply to Mostew]

Yes, I know , yet with so little to look forward to these days and the fridge being placed conveniently close to my new "office" (ie dining room) it is really difficult. Every day I get up saying "no more biscuits" and yet by about 2pm I've caved in...well, there is always tomorrow.

[Mostew in reply to MWxxxx]

I've been making cocoa, date nut balls . They are delicious, quick to make and can freeze some ..Also maybe a suger free jam or good honey with tahini on rice cake is nice .

Brazil nuts coated in dark chocolate.

Not same as biscuits but over time maybe you will replace them and enjoy other things .

Oh also I love cocoa, almond milk honey

Hot drink with cinnamon.

Don't feel deprived !!!!

[MWxxxx in reply to Mostew]

Thank you, these sound lovely. I will definitely give them a try. I start the day so well with porridge and frozen blueberries with a mid morning snack of bran flakes, kefir, nuts and pumpkin seeds. Its the after lunch slump that gets me every time. Some of those date balls or choc covered brazil nuts may just see me through! Thank you for taking the time to give me some suggestions.

[Mostew in reply to MWxxxx]

Slow and steady wins the race!

[falconered53]

Hi everyone.My cholesterol was beautifully low for many years after my PVJak2+ diagnosis, although it had been borderline, just below normal, for years before that. I patted myself on the back for improving my diet and exercise. Fast forward 9 years I had been on HU for a year and my cholesterol was back up. I did a little research and learned that any cytoreductive therapy for PV will eliminate the cholesterol reduction which was actually caused by the PV. Take the good with the bad, I guess!

Thanks for all your sharing.

Ellen

[EPguy in reply to falconered53]

INF is a type of cytoreduction, have you seen this association for INF also?

[falconered53]

I’ll dig out the article I found tomorrow and send you the link. Heading to bed now

[falconered53]

Hi ETguy,

I don't know if this will answer your question. But here's the article. It's old but still quoted in books on cholesterol.:Characterization of hypocholesterolemia in myeloproliferative … pubmed.ncbi.nlm.nih.gov › .

Here's also one about the reduced cholesterol phenomenon itself. Let me know if you have any thoughts about this. I'm not terribly good at understanding some of this stuff.

ashpublications.org/blood/a...

Good luck with everything.

Ellen

[EPguy in reply to falconered53]

Thanks. The 1st link is not a specific article. The 2nd one shows that lower chol, including lower of the good kind (HDL) relates to lower survival in PMF. Quite a strong correlation in this figure from the report.

No clear info on PV, ET. It is an old report (2007) partly seen by the use of "MPD" to describe the conditions. These days it's usually "MPN".

Chol vs PMF

[falconered53 in reply to EPguy]

I'm sorry the link didn't work. My computer skills leave much to be desired. Here is the abstract of the article:SaveEmailSend to

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Am J Med

. 1981 Oct;71(4):595-602. doi: 10.1016/0002-9343(81)90212-6.

Characterization of hypocholesterolemia in myeloproliferative disease. Relation to disease manifestations and activity

H S Gilbert, H Ginsberg, R Fagerstrom, W V Brown

PMID: 7282748 DOI: 10.1016/0002-9343(81)90212-6

Abstract

Characterization of the hypocholesterolemia observed in polycythemia vera and agnogenic myeloid metaplasia revealed significant reductions in plasma total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol in an age- and sex-matched comparison with the Framingham population. Men with myeloproliferative disease also had significantly lower total and LDL cholesterol levels than did those with relative or secondary polycythemia. LDL and HDL cholesterol were significantly correlated, suggesting a generalized disturbance of cholesterol metabolism, unexplained by nutritional status. Evaluation of the relationship among hematic cell proliferation, degree of myeloid metaplasia and hypocholesterolemia by multiple regression analysis revealed that spleen size was the variable of most significance in explaining the variation in plasma total, LDL and HDL cholesterol levels. Uncontrolled disease activity was accompanied by a decline in LDL cholesterol levels. Splenectomy or control of proliferation with chemotherapy or splenic irradiation reversed this abnormality. Levels of plasma total and lipoprotein cholesterol provide information that may be of value in diagnosis and assessment of myeloproliferative disease activity.

[EPguy in reply to falconered53]

Thanks. It seems to be from 1981. The ideas of splenetic irradiation seems archaic, but maybe it's still used somewhere?

But the Framingham study is a huge long term study of everything and anything from it is worth attention. If there are any updates since 40 yeas ago it is worth seeing.

[Mostew]

Re comments on bad habits . I’ve always eaten very well. Long before ‘whole foods ‘ were trendy

Done yoga etc .

BUT it has taken me many years to be more emotionally balanced .

Sub conscious stuff from childhood experiences effects our response to what life throws up . and of course anything negative throughout our lives

Turning difficulties into ‘what is this trying to teach me ‘ for me is useful.

Xx

[EPguy in reply to Mostew]

Chronic stress is a really bad habit, and fixing it can be quite helpful. But often easier said than done.

[Mostew in reply to EPguy]

VERY helpful ......It's hard cos patterns are so ingrained in us . Modern society values things that make fr more stress rto. We aren't meant to be so detached from nature...