TET2 Mutation

[Trueblue8]

I have ET JAK2 pos and take hydroxycarbamide and low dose aspirin. After a routine blood test I've been informed that I have another mutation known as TET2. Can anyone throw any light on this please, what is it and what does it mean?

Thanks

Ian

[EPguy]

TET2 is called a "non-driver" mutation, meaning generally that it does not cause MPN by itself. There are many other non-drivers with inscrutable letters.

Drivers are Jak2, CALR, and MPL. To confuse a bit more, triple negative (no drivers at all) can also be associated with ET.

They find non-drivers by doing NGS (NexGen Sequencing) where they look for anywhere from 25 to over 100 mutations. It's a good sign your Dr ordered this test as Dr is looking carefully for you.

You should also ask what your Jak2 allele burden is. (AB) This is roughly the portion of your Jak2 cells that are mutated. It is useful to know for future reference.

I did some searching on TET2. It does not show up that much in negative prognostics compared the other non-drivers . This report indicates it is a low risk mutation:

<<Mutations in the TET2 gene are the most frequently encountered in PV and ET and have shown no prognostic impact in previous studies>>

ashpublications.org/bloodad...

For comparison this report has other non-drivers that are negative prognostic:

<<Recently, a molecular high-risk signature has been developed in PV (SRSF2 mutations) and ET (SRSF2, SF3B1, U2AF1, and TP53 mutations)>>

But I recall TET2 was associated with reduced response to INF (interferon therapy) in CALR mutated ET and in PV in one report I came across.

Member Hunter has good insights on TET2. Others here likely will give you more info too.

[Trueblue8 in reply to EPguy]

Thank you for your reply, it's much appreciated. An interesting read!

[hunter5582]

The answer is a bit complicated. The short version is that TET2 appears to be a tumor suppressor gene that is involved in myeloid malignancies. Approximately 16 % of people with PV have TET2 as a non-driver mutation in addition to JAK2. Not sure about the numbers with ET or other myeloid disorders.

Thus, the tumor suppressor role of TET2 has been extensively documented, especially in myeloid lineages

ashpublications.org/blood/a...

Tet methylcytosine dioxygenase 2 (TET2; also known as ten-eleven translocation 2) is a gene that codes for methylcytosine dioxygenase TET2, a protein involved in epigenetic regulation of myelopoeisis (Gene 2014; PMID: 24220273).

mycancergenome.org/content/...

Here are a couple of other links worth reading

medlineplus.gov/genetics/ge...

nature.com/articles/leu201069

Suggest you look into the role of the TET2 mutation a bit more. Certainly talk to a MPN Specialist about it. Please get back to everyone with what you learn. We can all benefit from your knowledge and experience.

[Trueblue8 in reply to hunter5582]

Thank you for your reply, it's much appreciated and I will share any findings on the group.

One of my concerns is that I've got a tumour on my left kidney, which I've just found out is thankfully benign. Ordinarily I would be happy for this to be left as it is but I'm concerned that the TET2 mutation could potentially impact this tumour in the future, so I'm considering asking for it to be removed. I've read that the mutation can also affect solid tumours. Any thoughts?

Ian

[EPguy in reply to Trueblue8]

You bring up a good point, with additional mutations being proactive on any risk could be good planning. This is an example of TET2 you may be referring to:

<<Tet2 mutations drive tumorigenesis in several blood cancers as well as in solid cancers.>>

nature.com/articles/s42003-...

Here they state it as a driver, but in MPN it's not classically that, so more info is indicated.

--

Here is a good article that goes into detail on TET2 and blood cancers, with the same broad encouraging statement as the earlier link. It seems to have different effects depending on the specific blood cancer:

<<Large cohort studies showed that TET2 mutations did not impact the overall survivals in AML and myeloproliferative neoplasma (MPN) patients...TET2 mutant-CMML and -AML patients had poorer outcomes compared with patients without TET2 mutations...In contrast, TET2 mutations have been shown to confer superior survival in MDS>>

frontiersin.org/articles/10...

--

Here is a sample that includes some of the negative mutations listed above as non-driver MPNs, but here influencing other cancers. TET2 is not listed here:

<<Spliceosome gene mutations are highly recurrent in myeloid malignancies, CLL, and non-cutaneous melanoma, but they also occur in lung, bladder, and breast cancers. These occur most commonly in SF3B1, SRSF2, U2AF1, and ZRSR2>>

cell.com/cell/pdf/S0092-867...

[Trueblue8 in reply to EPguy]

Thanks for your reply. There's some really useful information there, although some of it is hard to understand!!Ian

[EPguy in reply to Trueblue8]

I agree on the understanding, nothing in our journey is easy to figure. The fine details like names, terms etc I don't sweat it, overall ideas are good enough for me. I do try hard to make sense of it.

My broad take from the above is TET2 is among the "better" non drivers, at least for MPN, while fewer of them in general is, not surprising, also better.

[hunter5582 in reply to Trueblue8]

As I understand it, the TET2 gene is tumor suppressor. I have a similar additional mutation, NF1. The NF1 mutation is a germline mutation that causes another condition called Neurofibromatosis Type 1. NF1 is a tumor suppressor gene. This is a loss of function mutation that causes an increased risk of tumors (neoplasms). NF1 is also a nondriver mutation for MPNs. The presence of the NF1 mutation increases my risk of progression to AML. While I have never had any of the neurofibromas (benign tumors) typically associated with NF1, I did develop a NF1-related brain tumor. A very rare Adult Pilocytic Astrocytoma. It was a true grade 1 tumor with none of the 27 cancer genes present.

The bottom line is that due to having both mutations, I am at increased risk of progression. I used to have ET, diagnosed about 30 years ago. It progressed to PV about 8 years ago. I made the decision to treat more aggressively with Besremi in part due to the evidence that the interferons reduce risk of progression.

Ultimately you will have to figure out what having the additional TET2 means for you and how you assess the risks/benefits of your treatment options. This would include the kidney tumor as well. The JAK2 mutation does increase risk of other neoplasms beyond the hemopoietic stem cells.

I would certainly review the findings with a MPN Specialist. If you decide to consider surgery for the kidney tumor, I would be sure to involve the MPN Specialist and also get a second opinion from another nephrologist.

At the end of the say it is your treatment goals and risk tolerance that are the determining factors. Please do let us know how you get on.

[Kauaiboy]

I had a nephrectomy 3 years ago for malignant cancer. MD told me they had no way of being certain whether it was benign or malignant and, since you can live a normal lifespan with 1 kidney, standard protocol is they take it out. I chose a total vs partial nephrectomy because of this statement. This surgeon was the Chief of Surgery of a major SoCal hospital and the Chief of Urology. Having only 1 kidney does have its negatives: Can’t take anti-inflammatory pills, cortisone, and I can’t clear the contrast dye used with a CT without a flush after, as I have 50% less clearing rate. I have to evaluate every single prescription and tell the MD to speak to my nephrologist first. E.G.: a routine arthroscopy turned into a hellish painful recovery because I could not take anti-inflammatories. There is another choice : a partial nephrectomy. Not many surgeons do this because it’s so intricate and in most cases the goal is to be sure your cancer free. But they are out there and if you truly are benign, I suggest you consider that option to preserve you clearing rate for the rest of your life as it will impact your diet, your medications and more for the rest of your life. I’m curious about how your MD was able to give you a benign report as my surgeon said they don’t do biopsies - I forgot why but I think it had to do about fear of spreading it or missing the cancer.

And I just got put on HU &aspirin for Jak2+ E.T. Not sure how 1 kidney influences this, but I’m sure it does in some way. I had a very harsh and painful experience 7 days ago that I believe was correlated with the HU as I stopped it for 2 days and quickly recovered. Currently in limbo waiting for Hemoc visit to discuss. I’ll be posting soon for sure. Good luck.

[Trueblue8 in reply to Kauaiboy]

Thanks for your reply. I had a biopsy carried out a couple of weeks ago, which confirmed the tumour to be an oncocytoma. My point with this is that I won't feel particularly at ease with having a tumour, albeit benign, with the added complication of blood mutations and also I don't know if they can tell whether it's precancerous or not? I'm seeing the consultant next week so will see what the options are. Ian

[Kauaiboy in reply to Trueblue8]

It's a great question. If it was cancer you would get it staged. According to my.clevelandclinic.org/heal... extremely rare for these tumors to become cancerous. Maybe active surveillance with regular scans? Adding ET to the equation is another ballgame.

[EPguy in reply to Kauaiboy]

That is quite an experience. HU is by design a toxin, so you will want to monitor closely with your Dr. I took it for over a year. That correlation does suggest potential concerns. Are you back on the HU, or is your limbo going without?

If it remains troublesome there are other options such as interferon (Pegasys or Besremi). Worth discussing with your Dr. whether there is a dose that could be ok for you. Likely insurance won't approve Besremi since it's for PV, but some ET patients here are taking PEG.

[Kauaiboy in reply to EPguy]

I really should not hijack this TrueBlue8 thread - I'm responding to EPguy. Should I repost?

EPguy - I stopped HU for 2 nights and resumed last night on 500mg. The flank pain is 95% gone now - it went down 80% in 12 hours. The right side flank pain started gradually after about a 7-10 days following a dose change to 1000mg MWF. The pain went from 2/10 to 9/10 in about 7 days. Originally I thought it was due to some physical labor I was doing but I realized the pain should be getting better not worse. I researched the correlation between back/side flank pain while on HU and discovered on Mayo clinic site that it was a possible side effect and to immediately notify MD. That was 3 days ago. I went to my primary 2 days ago and had more bloods: Platelets down to 540. But I see RDW at 17.1% (never been above 15) and also had a CRP 14.84% (dangerously high). The combination of both these bloods tests and last Friday's Bone Marrow biospy w/CT incidental finding (suspected mass in rectum last Friday) has me wondering if I might have a tumor. I have no cardio issues whatsoever and am normal BMI. Renal cell carcinoma nephrectomy and prostatectomy - both within 3 years.

I just talked to the RN. The Hemoc said to resume the HU at 500/1000 and see what happens. Seriously. I said I started 500ml last night and was anxious about doing 1000 again. Rn said she'd ask Hemoc and get back to me. I have an appt with the Hemoc in 8 days and CBC and CMP to do b4. We talked about the incidental finding and I am being referred back to the Gastro MD - I just had a colonoscopy 4 weeks ago after finding out about my elevated platelets. Had a sessile polyp scraped - benign. Gastro said I'll see you in 10 years.

To recap, this Dx and medical care all started about 5-6 weeks ago after burning feet and headaches, visual disturbances, numb toes. First off: CBC and CMP: 650 Elevated platelets noted, then routine colonoscopy, another blood test with positive for JAK2; then ER visit with ET/stroke like symptoms (only way I could get the Hemoc respond!) and put on 500 HU/aspirin; then 2 weeks later 750 platelets so -incr HU to 1000 MWF; then bone marrow biospy (& incidental finding); then extremely painful flank symptoms. I am used to managing a lot of things going on but never had this much action to deal with regarding my health.

Today I'm wondering can one have both Primary & Secondary ET? I have the Jak2 V617F mutation - and I may well also have a tumor. Anything is possible but what are the odds? I'm betting against.

And I have plans to leave in 2 weeks to our summer home for 3 months where I plan to see a bonafide MPN specialist. I'm doing all I can to make this happen. Praying for false alarm on the rectum mass.

[Ben2022]

I also have JAK2/TET2 mutation which upset me a lot . Have no idea whether this condition will transfer to MF or AML quickly. Some research hold that tet2 is not risky, while others argues it does do harm to OS.

[Trueblue8 in reply to Ben2022]

Hi Ben, I've been to see a genetics specialist and she said that they're unsure on the significance of TET2, but that it's a tumor suppressor. What I would take from that, is perhaps we are more likely to develop tumors - last year I had a benign kidney tumor, which was removed and I was also diagnosed with testicular cancer, which is thankfully now all sorted. I also have stage 1 prostate cancer. I live life to the full and generally don't worry too much, I'm regularly checked, which is good as I'm never more than 3 months from problems hopefully being identified.

By the way what does OS mean?

Best regards

Ian

[Ben2022 in reply to Trueblue8]

Thank you for your kind reply Trueblue! Sorry to hear that you have other cancer .Hope everything goes well. OS is short for overall survival.