FISH testing and chromosomes for dummies

I am betting most of us had a blood cancer tabula rasa at diagnosis, that is, our knowledge of blood cancer 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 blood cancer 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 blood cancer, simply put, it’s a test on a blood sample that looks at our chromosomes to see what type of blood cancer 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 it’s 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.