I am betting most of us had a cll tabula rasa at diagnosis, that is, our knowledge of cll was a blank slate. When told I had cll, all I heard was the word "leukemia". Google became my best friend and worst enemy. One of the first things I learned was that cll was not as bad as some other leukemias. But my cll learning curve had only just begun.
The relief I got from learning my leukemia might be treatable was short lived, google soon revealed that there are different types of cll, some worse than others. Oh hell. The four main types I learned had strange and somehow scary names: 13q, trisomy 12, 11q and 17p. Which one did I have? Why was I learning about it from google and not my doctor? What was a FISH test? Would my doctor order one for me? Would it hurt?
In a panic, I called my doctor and got through to his nurse. As it turns out, he had ordered a FISH test from my bloodwork and would give me the results at meeting the next week. Great. I spent my first weekend after my labs sweating out a test to see if I had cll. Now I got to spend another weekend wondering what variety cll I had. My new treaters at MD Anderson are much more sensitive to this.
So since this is a FISH test for dummies post, let's get to that simple answer fast. FISH stands for Fluorescent In Situ Hybridazation. As it relates to cll, simply put, its a test on a blood sample that looks at our chromosomes to see what type of cll we have. Cll is caused by one or more chromosomal abnormalities. FISH tells us which ones. That's all you need to know if you just want to know what a FISH test does. If you want to know more about what abnormalities we have with cll, read on, but prepare to be confused.
Remember cll cell biology for dummies? Cells are the building blocks of life with a nucleus and outer membrane. But how does a cell know what to do? How does a skin cell know how to make skin? How does a muscle cell know how to contract? How does a cell decide my eyes will be blue? You know the answer to that. Its in our cell's blueprints, their dna.
Inside the nucleus of each cell we have twenty three pairs of chromosomes, tightly coiled strands of dna. They are numbered one to twenty three, largest to smallest. Each chromosome is like a book filled with chapters of instructions to tell cells how to function. Chromosomes are shaped roughly like a misshapen X, with long arms and short arms. More on that later.
Genes are segments of dna. Any given chromosome might contain thousands of genes. If a chromosome is a book, like a cookbook with recipes, each gene is but one recipe. The genes pass along these instructions to cells to do their jobs. Genes do much more than decide if our eyes will be blue though. Genes carry instructions for everything from how our heart muscle contracts to how we use oxygen. We even have cancer fighting genes. These are genes that instruct cells how to fight cancer. All of our genes are named. One of our most important cancer fighting genes is named TP53.
When genes or chromosomes are damaged, we can have a problem. Our cells either get no instructions or bad instructions. Down's syndrome is an example of the result of a chromosomal abnormality.
Now lets talk about common cll abnormalities, 13q, trisomy 12, 11q and 17p. What do these numbers and letters mean? Why does 17p carry the least favorable prognosis? For that we have to go back and talk about chromosomes.
Remember when we said chromosomes have a short arm and a long arm? Chromosomes are in an X shape, but not a perfect X. The short arm of the X is called the "p" arm, its comes from the french word "petite". The long arm is called "q", just because q follows p in the alphabet. Let's also remember chromosomes are numbered, 1 to 23.
Anyone want to venture a guess what 17p deleted means now? It means chromosome 17 is missing part of its short arm, the p arm.
Now we have to remember that each chromosome is packed with little pieces of dna called genes. So if we are missing a part of a chromosome arm, then we are missing some genes at that location as well. So who can guess what important gene is on the short arm of our 17th chromosome? Its the TP53 gene, a cancer fighting gene so important it's nickname is "guardian of the genome". 17p deleted cll carries a challenging prognosis because when the p arm is deleted, an important cancer fighting gene goes with it.
A report of a FISH test can be confusing to read because it might reference a chromosome like 17p or it might instead reference a gene like TP53. But these are much the same thing, because the impact of being 17p deleted is losing the TP53 gene. The FISH report might also reference a cut-off percentage of 20% or something close to that. If only 2% of our cells are 17p deleted, that would be considered 17p negative on the report. We would not be considered 17p positive unless 20% or more of the cells examined were positive for a 17p deletion.
Another important cancer fighting gene we have is known as the ATM gene. Ever hear of ATM (not the banking machine)? Any idea what chromosome ATM is on? The ATM gene is on the long arm (q arm) of our 11th chromosome. If your FISH says you are 11q deleted, it means you are missing part of the long arm of your 11th chromosome. In turn you might have lost some of your ATM gene, an important cancer fighting gene.
Trisomy 12 is a different type of chromosomal abnormality. It occurs at the 12th chromosome and is added material instead of deleted material, hence the prefix "tri" for three. Normal chromosomes come in pairs. Downs syndrome is trisomy 21, an extra number 21 chromosome. You should be able to figure out 13q now. Its a deletion of the long arm of the 13th chromosome. 13q carries a more favorable prognosis because the genes located at 13q are not critical cancer fighting genes compared to the TP53 and ATM genes.
But wait, my FISH test talks about a 13q14 deletion. What's the 14 about? Well the q arm (long arm) of the 13th chromosome covers a lot of microscopic ground with a lot of genes. The number 14 in 13q14 describes the region of the long arm where the deletion occurs. That way scientists can narrow down exactly what genes are impacted. In 13q14 cll, it's the genes in region 14 of the long arm of chromosome 13 that are involved.
And it is helpful to know not all abnormalities within the same group are equal. Two people could have 17p Cll that acts quite differently partly because their deletions are different. One might have a large chunk of the p arm missing, another a smaller piece missing. They size of the deletion is important too. There are genes up and down the p arm and the bigger chunk of the arm we lose, the more genes we lose.
I hope I have not thoroughly confused everyone. Cll is a blood cancer caused by abnormal white blood cells who have lost their way because of abnormal chromosomes. Cll can be indolent or aggressive, depending on what chromosome is damaged and how badly its damaged. The FISH test looks for commonly known chromosomal abnormalities. A normal FISH test doesn't mean you do not have cll, it just means your do not have the common type cll FISH can find.
Its important to know that all this gene stuff has just been mapped and figured it. It has resulted in an explosion of cancer research to learn how to attack cancer at a cellular level. They are making amazing progress, with blood cancers in particular, in using this new found understanding of genes and chromosomes to treat and cure all sorts of cancers.
Finally, I do not have any science or medical background and I am sure my analogies are imperfect. In the process of dumbing this all down so I can understand it I have probably mixed up some facts and confused others. I hope its close enough to be accurate and simple enough to not be too confusing. Chromosomes, DNA, and genes, oh my. Its an intimidating subject to dumb down.
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cajunjeff
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I might just complete the picture for someone getting their FISH results and it states, 'Normal Karyotype'. This only means that the chromosomes that have been looked at - 11,12,13 &17 are normal. We know we have CLL by something called 'Flow Cytometry'. However, there has to be something abnormal with a chromosome(s) somewhere, it is just not looked for with the FISH test.
Thank you Jeff. My husband just got diagnosed with PLL and I was so confused wading through all these numbers and letters but you did a great job explaining and it is so helpful.
Master communicator Jeff, you make a good case for explaining stuff.
Thank you!
I am of the persuasion stuff understood is stuff we worry less about.
Explaining stuff neutralises uncertainty. Makes for a better life.
Many of us rest in the belief that our Drs "have our 6"! Nevertheless I feel for your anguishing waiting 2 weeks for a diag and then which CLL.
Here in the UK - FISH is not normally done till treatment is planned. That makes the British Want and Wait a little more arduous - we dont get to know which CLL type we have. The reason for that is that CLL is "fluid". We know that FISH needs to be repeated before each treatment plan - possibly less need now the new treatments kick in. FCR is not given to 17p etc.
I am waiting for your next chapter - mutated vs unmutated - possibly
I absolutely love this! Because I go next week to discuss possibly entering a research trial and someone in my face to face support group said mutated 13p del /mutated doesn't usually respond well to early treatment SO I go home to see if my original Hem gave me the fish report. And I'm bummed because I cannot find all of it (or was never provided it). I just know I'm mutated, which sounds like something out of an Avengers movie! Anyway, I appreciate your research as I've been reading articles all week. I remember loving the science lessons in high school on genetics but in an ironic sense I thought, who knew where this interest would lead me later on and that mutated would be a GOOD term? So my oncology appointment is next week so I know I'll get my "13p, 17p, trisomy" answer there, but in the words of Tom Petty "the waiting is the hardest part". Thank you for taking time to post this info!
This was brilliant. It would be cool to pair up with someone with artistic talent and make this a slideshow or an ebook. With art that keeps the slightly whimsical tone. I'm completely without artistic talent unfortunately.
Jeff this is amazing! Even with a masters degree in nursing I have never understood this until now. Please continue to explain things to us! Thank you so much!
Thank you. I’ve always read these things and (being in the U.K. so I don’t know which I am) let the terms and numbers wash over me - now I understand! I also don’t know if I’m mutated or not, but standing on one leg in my daughter’s kitchen with my tongue stuck out and my eyes crossed, my daughter (a microbiologist so she should know) reckons I’m definitely mutated - or maybe just strange. Keep well everyone - to those of us in the northern hemisphere spring is on its way....
Thank you Jeff. Your explanation was excellent and, as I was reading through, the pictures of all those twisted imperfectly formed arms of X were pictures in my mind.
I am Trisomy 12 and started to think what does that third arm do? Is it inhibiting the function of whatever chromosome 12 is suppose to do?
I am going to read this over again. You have a gift to explain this minefield of CLL we are slugging through 👍🏻
It’s confusing to me. As I understand it, the big issue with 11q is the ATM gene and the big issue with 17p is loss of the TP53 gene. I think the gene involved with trisomy 12 is the Notch gene, but how the extra chromosome interferes with the function of the Notch gene is over my head. I don’t think everyone with trisomy 12 has the notch mutation, which might explain why the prognosis for trisomy is so variable. I am guessing those without the notch mutation do better on average.
Deletions are conceptually easier to understand than trisomy for me. I think trisomy can occur at other chromosomes as well and when it is present at birth can cause a variety of issues. I assume with Cll we acquire our abnormalities over time, although we might be born with some predisposition, which would explain why Cll can run in some families.
Thanks so much. I have trisomy-12 and a mutated med-12 gene. I’m told that in a sample of 500 cases, this mutation would probably be found 6 times. I’m not showing notch1 or 17p.
I was diagnosed in 2016 and have had very few symptoms other than a massively runaway white blood cell count. Recently my red cell values were wildly off and my hematologist has started me on obinutuzumab—venetoclax thinking that there must be some sort of yet-unknown notch1 function somewhere.
Thanks for your post. It’s all starting to make sense.
Hi Jeff, I have wondered if our chromosomal abnormalities are the cause of our CLL or a symptom. Also when do our CLL cells get the abnormality? At the maturation stage when the DNA is being shuffled or mutation stage? Downs syndrome people are born with trisomy 21, but I assume my trisomy 12 was acquired later in life. What causes that? Do we still produce some normal B cells?
I don't know the answer to this. My best guess is that most of acquire these chromosomal abnormalities after birth. Maybe there is an environmental cause like round up or agent orange. Maybe it is diet. Maybe its something our genetics predispose us to have.
We know that cll can run in families, so these is probably some inherited genetics that play a role as well. To what extent, I am not sure anyone knows. I agree that that your trisomy 12 was acquired after birth, not present at birth as it is with downs syndrome which is trisomy 21, an extra copy of chromosome 21.
It is beyond amazing the code that is packed into the tiny nucleus of a tiny cell that determines who and what we are. We have some 20000 genes that code for who we are, its amazing we don't see genetic defects more often like two heads and six toes and so many more subtle defects as well.
I can take a guess. Chromosomes come in pairs. Normally for every one gene we get from one parent, we get a corresponding gene from the other parent. These genes are called alleles.
We might get a brown eye gene (allele) from one parent and a blue gene (allele) from another. Since the brown is a dominant gene, our eyes would be brown.
I am guessing a monoalleclic 13q deletion is where only one gene (allele) is deleted, bialleclic where the same gene from the other parent is deleted too. If I have an ATM gene on one strand of chromosome, I have an ATM gene on the corresponding strand because chromosomes come in pairs.
I don't think a bialleclic deletion carries any worse prognosis. There is some thought out there that a higher % deletion can carry a worse prognosis.
But I am just giving you an educated guess. I would assume if your only FISH abnormality is 13q as you describe, I would think that carries a favorable prognosis. If someone has 13q and 17p, the 17p would trump the 13q.
Jeff you said educated guess, I can tell you are one smart guy, even though you said you didn't do well in science, I bet you really got an A in that class.
Wow!!! You’ve taken a complicated piece of science and made it so easy to understand. I think that you should go into business and author some medical pamphlets. Well done and many thanks 😊
Jeff - that was an outstanding and crystal clear explanation of a complicated subject. When I was diagnosed initially with SLL it was through a lymph node biopsy and flow cytometry. My doc never mentioned FISH or Ighv mutation testing. Through this forum (and the wonderful world of google), it was clear that it's so important to get these type tests to get data points on each person's individual prognosis and potential treatments. It reinforces the need to make sure we find docs that have CLL/SLL expertise. Thanks again!
This was very reminiscent of the wonderful monthly seminars given by Chaya Venkat. If Chaya was still active in our community, you would be the star pupil.
Please - continue to analyze the tests and share your explanations..You are gifted in the concept of *KISS* - keeping it simple. Really works for me.
It would be helpful for you to explain - in your style *mutated vs unmutated*.
I love #thompsonellen’s suggestion for an ebook or slideshow.
Have I inspired you to spend more time with Dr Googala? (Hope so & lucky for us!)
Diana, I was lucky early on to stumble upon Chaya’s Cll blog. The comparison is flattering, but it’s apples to oranges. Chaya is a pro who understands this stuff exponentially more than I do. I have to read over it many times and figure how to dumb it down to where I can have some idea what they are even talking about.
I have been mulling over mutated v unmutated and will take a shot at it. On one level it’s not too complicated, on another it’s way, way, way over my head.
But it is nice to know some on here find my over simplifications helpful, indeed it’s helpful to me because I need to dumb things down for me to pass it on.
I like Chaya’s blog because it’s so good at dumbing things down, but Chaya gets this stuff on a level light years over me. I have to dumb down what Chaya dumbs down, if that makes any sense.
Very good - this is the type of info we all needed when first diagnosed, and very helpful summary to review. I'd love to know more about 'extra material of unknown origin' added to some mutant chromosomes and where it comes from, other than that it is such a scrambled mess that they merely refer to it that way and nothing more.
I've had CLL since 2013 and started treatment last year. This series is excellent! However, the link you listed under "mutated/unmutated" is the same link for the chomosomes. Can you insert the correct link? Thank you SO much!
6q is not a common chromosomal defect with cll. I do not think the number of any chromosome in and of itself has any prognostic implications. That is to say, the fact 6 is a lower numbered chromosome that 11, 13 or 17 is not what is important. What is more important would be what gene is located on the q arm of the 6th chromosome that is impacted with cll and what is the function of that gene.
In terms of prognosis, I think 6q cll is thought to have an intermediate prognosis - better than 17p or 11q but not as good as 13q.
Of course its important to remember these are generalizations. Someone with 6q cll could do better than someone with 13q, markers are no guarantee of anything either way.
I suspect 6q cll might be under reported since its not a defect some FISH tests are even programmed to look for to find.
Hi Jeff, I went all over in internet and books to try to find out about FISH test for CLL. Just got all confused , too scientific and after reading I got lost. Your explanation was so easy to understand and easy to remember. Thank you so much .
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fish testing or lack of
CLL FISH tests results 
Need help understanding results
My CLL Specialist seemed concerned. I need help understanding test results. 
