Are there different tests for IGHV mutation? PCR? Sanger? NGS?
My PCR test report says no mutations detected. Should I retest with other methods?
Also, is IGHV mutation status innate or developed during the lifetime? If it’s innate and genetic, since I’m unmutated, should I get my children tested for IgHV mutation status to monitor them for CLL development?
Hi nuji,-
This area of genomics is the most confusing for many of us.
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The simplest answer is that IgHV is the one test where being Mutated is good.
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As B-cells develop and mature normally, they go through chromosonal / DNA changes that allow them to develop specific antibodies for specific diseases. So an UnMutated IgHV indicates a CLL cancer clone that developed earlier in the maturation process. You might think of it as a 13 year old hyperactive teen, lots of hormones and lack of control.
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If the CLL cancer clone develops later, after the CLL cells have been through the Mutation process analagous to puberty, they are more like an 18 year old teen, calmer but not fully mature. This results in a cancer that grows slower and is more predictable.
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As far as testing your children, I believe that the IgHV testing can only be done on a significant number of CLL cancer cells, so until cancer develops you can't test for mutation status. While CLL and other blood cancers do run in families, only about 10% of CLL patients have close relatives with blood cancer.
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You may want to advise them that they could have a slight tendency to developing a blood cancer, but that would likely be after middle age, and early detection is not important.
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As far as retesting, I suggest you ask your Hematologist to interpret the test results wording to advise whether the test was successful and means you are UnMutated or if the test failed to develop a reliable result. If you ALC is fairly low, the tests can be inconclusive. And prognostic tests like mutation status only advise whether you will need treatment sooner and more often (UnMutated) or if you will be in watch & wait for a longer time (Mutated). The rate of rise of your ALC can provide a similar and possibly a more accurate prediction of your TTFT (Time To First Treatment).
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Len
Thank you. I wish my ALC was not large enough to detect anything 🤞🏽. Shall check with the onco during next visit.
Funnily enough, don’t know why people determined unmutated is worse than mutated?? 🤪😅
UnMutated suggests that the CLL cells propogate faster and the ALC will climb quicker, and treatment will be needed sooner and more often. -
Mutated predicts a slower growing cancer and longer times before and between treatments.
Over the last 5 years I have seen numerous Kaplan Meier charts en.wikipedia.org/wiki/Kapla...
in clinical trial papers that confirm that TTFT (Time to First Treatment) or PFS
(Progression Free Survival) is shorter for UnMutated patients like me.
What has not appeared yet is any data on OS (Overall Survival) when the newer targeted treatment are used.
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BUT like almost all prognostics in CLL, those are generalizations/averages for large numbers of patients. A specific individual patient can be an outlier- very different than average.
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My own unproven theory is that the rate of rise of you ALC is a better predictor of your specific cancer TTFT, than either your FISH results or Mutation results. But I am not medically trained and not a statistician.
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This whole subject can best be discussed with your Hem/Onc, and hopefully he/she is a CLL expert with lots of experience and will take the time to explain fully.
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Len
Any logic why IGHV mutation status is stable? Why can’t unmutated IGHV get mutated on a later date?? If Richters transformation is possible why not unmutated people become IGHV mutated as time progresses??
That is well beyond my reading & understanding history, perhaps gardening-girl might suggest an answer from her genetic knowledge. Len
nuji, somatic hypermutation, which is the process by which IGHV genes become mutated occurs by a random process involving enzymes that are highly specific to a certain stage of B cell development. It predominantly affects immunoglobulin genes in B cells, and does not occur in other cells in your body, not even in T cells. The B cell that gave rise to your CLL clone had apparently not yet reached the somatic hypermutation stage, as lankisterguy said. The term somatic implies that the hypermutation does not occur to germ line genes.
So what protects all of the other thousands of genes in B cells? And what protects the constant region of the Immunoglobulin genes from the crazy enzymatic hypermutation? Great question. There are some interesting theories. 😀
My lay understanding: when you have unmutated CLL cells and they keep making copies of themselves then how do you want all those copies to become mutated? All of them would have to continue maturing and that is exactly what they do not do. That is why they are CLL cells and not regular b cells.
My layman understanding is/was that cancer is a mutation where cells don’t stop multiplying and autophagy is avoided + cancer don’t die (apoptosis) easily. So if one is unmutated, I assumed that all should be ok and there should be no cancer. While I know that mutated IGHV is better for CLL prognosis, the confusion is that - wasn’t it the mutation which caused the CLL in the first place? If the genes were unmutated, how did the cancer start? I guess the mutation for CLL to begin is not the IGHV mutation, but some other mutation. Along with the mutation for CLL to begin, if IGHV also mutates it’s better prognosis??? Is this statement correct??
IGHV 'mutation' is the normal somatic mutation process that maturing B-cells go through. It's how germline B-cells - the cellular DNA we inherit from our parents, is modified to produce the billions of different B-cells with unique B Cell Receptors. There are two theories about how the IGHV gets mutated in CLL. The long held theory is that CLL cells arise either before or after the somatic hypermutation phase, with more mature cells correlating with more chronic leukaemia. (Leukaemias that occur earlier in the life cycle are more acute.)
The more recent theory is that the IGHV mutations in the CLL DNA are due to the better DNA correction, hence more stable disease.
CLL cells indeed have some form of DNA mutation, with the most common mutation types detected by FISH testing.
Neil
nuji, I think that the use of PCR (polymerase chain reaction) is simply to amplify the CDR3 region of your IGHV gene so that it can be sequenced and compared to the germline sequence. If you are interested you can read this article titled:
IGHV Mutational Status Testing in Chronic Lymphocytic LeukemiaAm J Hematol. 2018
ncbi.nlm.nih.gov/pmc/articl...
If you do ask for clarification from your oncologist you might ask to which subset/isotype your BCR /IGHV belongs. Whoever analyzed your CDR3 for mutations would have had to pick one of the germline subsets to compare the sequence of your CDR3 with. For information about that take a look at:
The importance of B cell receptor isotypes and stereotypes in chronic lymphocytic leukemia
Leukemia 2019
nature.com/articles/s41375-...
Thank you. I will enquire with my Oncologist
‘A patient’s IGHV mutation status is a key factor in CLL prognosis. Doctors looking for a patient’s IGHV mutation status are looking at the age of the cell that allowed CLL to grow. If it is a younger, unmutated cell, it will likely be more aggressive. If it is an older, mutated cell, those tend to be slow-growing.This information helps doctors determine which type of treatment to use. Typically, a patient with a mutated IGHV cell will go into remission for 10 to 15 years after initial treatment while a patient with an unmutated cell will typically only have 3 to 4 years of remission.
Dr. Matthew Davids, Associate Director of the CLL Center at Dana-Farber Cancer Institute, says newer drugs like Ibrutinib, Idelalisib and Venetoclax tend to be more effective at treating un-mutated IGHV cells and offer some promise for the future.’
survivornet.com/articles/wh...
In response to your question as to whether our IGHV status remains unchanged throughout our lifetime, the surrogate IGHV status is often obtained during flow cytometric analysis. It’s said that whilst CD38/ZAP 70 expression remains stable over time in the majority of patients, it is known to change in approximately 25 percent of cases. We have had patients whose mutational status has changed and sometimes the initial result is inconclusive (as in my case).
Newdawn
As someone who is unmutated, I got hung up on the nomenclature. It made no sense to me. I wish they'd just call mutated “lucky” and unmutated “yucky,” that would be easier. I've found this video interview with CLL specialist Dr. Tam and Dr. Brian Koffman discussing mutation status especially helpful. Dr. Tam agrees that the names sound like the opposite of what they are.
cllsociety.org/2018/05/ash-...
I would just add that a CLL specialist knows that unmutated patients should not receive chemo treatments (tho I wasn't that "lucky" with my last CLL specialist).
I’m totally with you on the nomenclature 😃
17p deletion IGHV unmutated tp53absent
HOW DO WE DETERMINE MUTATION STATUS?
Need help reading test results - mutated vs unmutated
IgHV - unmutated and Acalabrutinib
Would like CLL Specialist in BC - Private pay for IGHV?
