Technical terms I am unfamiliar with

[markjeep51]

In my original diagnostic testing of 2013, it states, " Somatic hypermutation analysis showed two clonal populations with one of which was VH1-3 which was unmutated (0%) and the other was VH3-30 which was mutated (7.3%). FISH analysis showed 13q14 deletion which was monoallelic in 19% of cells and biallelic in 16% of cells." I have no idea what all this gobbley-goop means; for example, "somatic hypermutation analysis", "monoallelic" and "biallelic" ? Could someone provide some insight? Also, does a VH3-30 mutation have any prognostic meaning; what is it ?

[cllady01 Former Volunteer]

. I think (to the best of my knowledge, which is not at lot) Somatic Hypermutation is showing the flexibility and extent of your immune systems ability to cope with what is thrown at it.

The following will give you something to read while others who are more erudite on the subject can break it down and define better some of the involved mechanisms of CLL.

"Somatic Hypermutation diversifies B cell receptors used to recognize foreign elements (antigens) and allows the immune system to adapt its response to new threats during the lifetime of an organism."

en.wikipedia.org/wiki/Somat...

[AussieNeil Partner Administrator]

Somatic hypermutation is the DNA altering process B-lymphocytes go through so that they can make millions of different B Cell Receptors to find one that keys to an antigen, e.g. a unique part of a bacteria, fungus, virus. This is hypermutation happens in the IGHV@ gene. When a B-lymphocyte matures into a plasma cell, that part of the B Cell Receptor that keys to the pathogen is incorporated into billions of immunoglobulins churned out into the blood stream - IgA, IgG or IgM.

When we talk of CLL being 'mutated' or 'unmutated' it's a shortcut for stating whether the CLL cell has been through the somatic hypermutation process.

Our DNA is formed from paired copies of genes from both our parents - biallelic. When DNA is copied, sometimes only one allele is copied, hence monoallelic:

nature.com/scitable/content...

Provided that one allele is functional, there's generally not a problem, but if there's mutational damage, then treatment reliant on that section of the DNA being functional to trigger cell apoptosis will fail. That's why chemo treatments are reliant on the TP53 gene on the 17p chromosome being functional on at least one allele. I think I have that right . gardening-girl is our resident expert on these matters.

Neil

[Cllcanada Top Poster CURE Hero in reply to AussieNeil]

Great explanation Neil...a 'must read' 👍🏼

~chris

[markjeep51 in reply to AussieNeil]

Thank you for the reply !! Am just about there in my understanding. But being a retired engineer, I am wondering whether I should have this Somatic hypermutation analysis performed again on these two clonal populations; VH1-3 [ which was unmutated (0%) ]and the other VH3-30 [ which was mutated (7.3%). ] Since I have a very nice and understanding oncologist at the Veterans Administration in the USA, he is typically willing to perform just about any test I request. As an engineer, I would be curious what any potential variation over time, these two parameters might mean. I would also like to consider requesting to have this FISH analysis re-run to demonstrate any variation in the monoallelic [ in 19% of cells ] and biallelic [ in 16% of cells]" might mean. I realize that further understanding this aspect will not delay my likely eventual treatment but it may give me some pleasant satisfaction in understanding what is really going on in my body. Any further thoughts on how I could possibly enhance this line of logic to my doctor?

[Cllcanada Top Poster CURE Hero in reply to markjeep51]

FISH panel is probably worth running again prior to treatment because it can change as CLL progresses.

Might look at subclones, see if you harbor any poor ones, like NOTCH1, SF3B1, MYC and so on...there are a number of them, many are not fully understood.

Stereotypes VH genes from the IGHV family are unlikely to change, that's yor VH3-30;etc.

You want a TP53 mutation test before treatment.

Whole genome sequencing is very unlikely to be done now, but might be in the clinic in the next 5-10 years... then much more of the story will be told...

Much of CLL is unknown, and it seems every five years or so we get a knowledge 'bump-up', based on my 20 years with this cancer. Millions of patient specific epigenetic changes need to be traced, and work goes on in the field of inherited risk of disease. So too, predisposition and environmental triggers....There are lots of smoking guns in CLL but the bullets are rarely found....

~chris

[gardening-girl]

markjeep51, It looks like you have gotten some good answers to your questions. I only have a little to add. You asked about whether the VH3-30 mutation had any prognostic meaning.

First of all the 7.3% deviation from the germline is great since there is evidence that the greater the deviation the better the prognosis.

Then there is this:

"....comparing a series of stable and progressive CLL from our institute, VH3-30 was significantly overrepresented in patients with stable rather than with progressive disease. Thus, VH3-30 might be suggested as a marker of very indolent disease.

"

“Spontaneous regression of chronic lymphocytic leukemia: clinical and biologic features of 9 cases”

bloodjournal.org/content/bl...

The paper above focused on 9 cases of spontaneous regressing, but included many more in the analysis that led to the statement above about a correlation between VH3-30 and indolent disease.

All good news for you!

gardening-girl

[markjeep51 in reply to gardening-girl]

Thank you very much for your input. But probably a stupid question: It seems to me that a 7.3% deviation from the germline for VH3-30 would represent a very low number. A number in the 90% range would seem to be a big number. What am I missing? Thanks Mark

[gardening-girl in reply to markjeep51]

I totally understand why you might think that but in fact, if it differed from the germline sequence by 90% it would be a totally different gene! Somewhere I've bookmarked a web site that would demonstrate the different germline families, but I haven't found it yet.

[markjeep51 in reply to gardening-girl]

You are a great teacher !!! Thanks Mark

[gardening-girl in reply to markjeep51]

Mark, here's an explanation of why I say at a 90% deviation from the 3-30 germline sequence you would have a different gene, and not a 3-30 IGHV.

IGHV genes are divided into clans and subgroups based on their DNA sequence, which is based on the way the genes have been assembled during V-(D)-J rearrangement. See the link below for an example of the assembly process.

oregonstate.edu/instruct/bb...

oclan I: IGHV1, IGHV5 and IGHV7 subgroup genes

oclan II: IGHV2, IGHV4 and IGHV6 subgroup genes

oclan III: IGHV3 subgroup genes

Each subgroup is further divided, hence subgroup IVIG3-30. Since all of the subgroups are all being made from various rearrangements of a single gene there is a lot of overlap in their sequences. Hence if you get much past a 10% deviation from germline, the sequence is likely not to belong in the IGHV3-30 subgroup at all and probably should have been compared to another germline subgroup.

I didn’t find the table that I was looking for but was able to get the information that I wanted to share with you. At the VBase site (vbase2.org/vbdownload.php) I was able to get the germline sequence for IGHV3-30. I then did a BLAST search at (blast.ncbi.nlm.nih.gov/Blas... which aligned the IGHV3-30 sequence with other IGHV germline sequences in the database. Here are three examples of what I found:

The IGHV3-43 sequence deviates 16% from the IGHV3-30 germline sequence; the IGHV3-22 sequence, 20%, and the IGHV1-3 sequence.28% IGHV3-30. So, clearly if your IGHV gene showed a 90% deviation from IGHV3-30, it never should have been compared to the 3-30 germline to begin with! Does that make ANY sense?

I tried to copy and paste the DNA sequence alignment (about 300 nucleotides) into this message but the formatting was so messed up that it wouldn't make any sense to you.

Just be happy about your 7.3% mutated status and forget about wanting to get to 90%!

gardening-girl

[markjeep51 in reply to gardening-girl]

Am starting to understand; so I promise to be happy with my 7.3% IGHV3-30 status: I promise. Have started reading (slowly) the "Spontaneous regression of chronic lymphocytic leukemia: clinical and biologic

features of 9 cases" article you provided which provides evidence that having the mutated IGHV3-30 gene may have a beneficial prognosis factor. It's a highly medically technical article but will do my best to get through it. Once again, you have gone far and beyond what I was expecting you to do for me !! Am hoping others might read our correspondence chain; for my specific situation, knowing these facts has calmed me down a bit.

[gardening-girl in reply to markjeep51]

Mark, please don't think that you need to wade through the spontaneous remission paper. It is a habit of mine to document things that I comment on. I have no medical background, just molecular biology, and am only commenting on things that I read and understand. Don't hesitate to ask questions that you might have and please do stay calm!