Prognostic and Genetic Markers
Professor Patrick Thornton, in his excellent presentation at CLL Ireland’s 2019 Patient Information Day, stated:
“The only prognostic factor that really influences treatment is p53”
“25% of patients will not progress and never require treatment. More likely to be: Female, 13q deleted, CD38 and Zap 70 negative, Mutated IgVH”
But what does all this mean?
The basic units of heredity passed down from your mother and father are genes.
Our genetic information is stored in 23 pairs of chromosomes that vary widely in size and shape. Chromosome 1 is the largest and is over three times bigger than chromosome 22. The 23rd pair of chromosomes are two special chromosomes, X and Y, that determine our sex. Females have a pair of X chromosomes (46, XX), whereas males have one X and one Y chromosomes (46, XY).
Chromosomes are made of DNA, and genes are special units of chromosomal DNA. Each chromosome is a very long molecule, so it needs to be wrapped tightly around proteins for efficient packaging.
Chromosomal changes
Cells that have chromosomal changes are detected by the FISH (Fluorescent in Situ Hybridisation) test.
The FISH test is used to look for certain genes or chromosome changes (not just any change). It can be used on regular blood or bone marrow samples, too. Because the cells don’t have to grow in the lab first, you can usually get the results more quickly than if they were grown in the lab, often within a few days. 
It uses special fluorescent dyes that during the FISH test process only attach to specific parts of particular chromosomes, that make the DNA glow in different colours when special wavelengths of light are shone on it.
FISH can help identify specific genetic defects by looking at where the colours are, to determine if they are in the wrong locations, relative to other colour markers. The location of the FISH colour markers can help your oncologist/haematologist determine a prognosis and possibly treatment for your CLL.
Deletions
In some cases, part of a chromosome may be missing. This is called a deletion.
The most common deletions occur in parts of chromosomes 11, 13, or 17.
CLL Patients with Chromosome 17 deletion 17p (“del17p”) tend to have higher risk disease. Their CLL treatment needs to be approached in a different manner than patients without del17p. These patients respond well to the new novel therapies.
1 in 10 CLL patients test positive for del17p.
Other, less common chromosome changes include an extra copy of chromosome 12 (trisomy 12) or a translocation (swapping of DNA) between chromosomes 11 and 14 [written as t(11;14)].
Mutational Status – Mutated vs. Unmutated
A gene mutation is a permanent alteration in the DNA sequence that makes up a gene, such that the sequence differs from what is found in most people.
Mutations range in size; they can affect anywhere from a single DNA building block (base pair) to a large segment of a chromosome that includes multiple genes.
It is critical for CLL patients to know whether certain genes are mutated or unmutated and tests to identify these should be carried out before any treatment commences.
The most important tests for CLL patients are to identify mutations in the TP53 and the IgHV genes. The mutational status of these genes will determine how patients will respond to certain treatments for their CLL.
TP53 Status
The mutational status of the TP53 gene is looked at in a test called the TP53 test which looks for a change in the TP53 (Tumour Protein 53) gene.
The TP53 gene provides instructions for making a protein called tumour protein p53 (or p53). This protein acts as a tumour suppressor, which means that it regulates cell division by keeping cells from growing and dividing (proliferating) too fast or in an uncontrolled way.
What happens during a TP53 test?
A TP53 test is usually done on blood or bone marrow.
If you are getting a blood test, a health care professional will take a blood sample from a vein in your arm, using a small needle. After the needle is inserted, a small amount of blood will be collected into a test tube or vial. You may feel a little sting when the needle goes in or out. This usually takes less than five minutes.
If you are getting a bone marrow test, your procedure may include the following steps:
- You’ll lie down on your side or your stomach, depending on which bone will be used for testing. Most bone marrow tests are taken from the hip bone.
- Your body will be covered with cloth, so that only the area around the testing site is showing.
- The site will be cleaned with an antiseptic.
- You will get an injection of a numbing solution. It may sting.
- Once the area is numb, the health care provider will take the sample. You will need to lie very still during the tests.
- The health care provider will use a special tool that twists into the bone to take out a sample of bone marrow tissue. You may feel some pressure on the site while the sample is being taken.
- After the test, the health care provider will cover the site with a bandage.
- Plan to have someone drive you home, since you may be given a sedative before the tests, which may make you drowsy.
IgVH Status Test
The mutational status of the IgVH gene is looked at in a test called cDNA sequencing.
Immunoglobulins, the antibodies that help your body fight infections, are made up of light chains and heavy chains. Whether the gene for the immunoglobulin heavy chain variable region (IGHV or IgVH) has changed (mutated) can help your doctor know how aggressive your CLL is.