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Alert Number 136

FISH, "Normal" Karyotype, and Clonal Evolution

Date: November 11, 2005

Our Topics Alert (#135) of a couple of days ago generated some questions about the nature of the FISH test. These are important questions, and all too often, the scary thing is it seems we are educating our local healthcare providers about new developments, rather than the other way around. Ignorance or inaccurate information on this front can lead to inappropriate therapy, and that is definitely not good for your health. Your oncologist loses a paying patient, but you may lose your life. You get my drift? You have most skin riding in this game.

The FISH test is an important prognostic indicator, both because of its ready accessibility, lower cost and dependability. The IGVH gene mutation test is harder to do and more expensive and testing for ZAP-70 is still a work in progress. More often than not, ZAP-70 results vary from lab to lab, and right now I would not hang my hat on this indicator. FISH looks for chromosomal aberrations. These aberrations are at the heart of every cancer. Chromosomal defects are what make cancer cells mutant cells that do not obey the normal rules of healthy cellular behavior. The fact that you have been diagnosed with cancer means that there is one or more chromosomal defect(s) in your cancer cells. This is a fact of life, there are no ‘ifs’ or ‘buts’ about this.

Each type of cancer has its own typical set of chromosomal defects that are characteristic of that particular cancer. And that is true for CLL as well. We do not yet know all of the chromosomal defects that can lead to the development of CLL. We know some of the more common ones. As research progresses, we will no doubt discover other defects, learn how to test for them, learn their prognostic significance. Right now, we know that the majority of CLL patients have defects in their 13th, 12th, 11th and/or 17th chromosomes. A given patient can have one or more of these defects or he may have a defect that we still know nothing about. More recently, defects in chromosome 6 have been identified in CLL patients. But this is still a relatively new finding and most commercial labs do not test for it. I am trying to get Quest Diagnostics to add testing for defects in chromosome 6 to the set of probes that they presently use in their prognostic package - see Prognostic and Monitoring Test Packages.

The generic CLL FISH panel therefore often looks for only these four chromosomal defects: 13q, 12 trisomy, 11q and 17p. If none of the above four defects are detected, the lab reports this as a “normal” karyotype, but as you can see that is a not an accurate description of the actual state of affairs. It just means the patient in question has one or more chromosomal defects that we do not know about and have not tested for. A more accurate description of a CLL patient who does not have any of these 4 defects would be “unknown chromosomal defect or defects”. We lump all the CLL patients who have “unknown” but very real defect(s) into one group, and call them “normal”. Since your have the big “C”, it goes with the territory that your CLL cells have one or more chromosomal defects. Whether we know what the defects are, or whether we know how to test for them, or bother to test for them, those are questions that your CLL cells do not care about.

This explains why folks with “normal” karyotype have worse prognosis than those with 13q deletion. Since “normal” actually means a bunch of defects we know nothing about, the empirically observed poorer prognosis of this group represents the average prognosis of all these unknown defects. “Normal” karyotype is a catch-all category at this point. Since we have no way of judging the unknown, a patient with a relatively less dangerous unknown chromosomal defect can do a lot better than another patient who has a more dangerous and equally unknown defect. That is the luck of the draw.

Another question that has been raised is the risk of clonal evolution. This refers to gradual addition of new defects to the defect you may have had to begin with. Clonal evolution is a fact of life with CLL, and unfortunately it is a slippery slope that seems to be all about picking up more dangerous defects over time. Many of the standard chemotherapy drugs can accelerate the process of clonal evolution. Fludarabine, for example, has been cited for selecting for 17p deletion, the most dangerous of the defects of which we know.

But even without the help of chemotherapy, clonal evolution can happen over time. CLL cells are genetically unstable, a classic feature of most cancer cells. Recently, it has been shown that clonal evolution happens more frequently in patients with the IgVH unmutated variety of CLL, and less frequently in patients with mutated IgVH. This is one of the reasons why mutated IgVH is an indicator of better prognosis, since it seems to give some degree of protection from clonal evolution to more dangerous chromosomal defects. Remember though, we are talking statistics here. A given individual patient with mutated IgVH can still have clonal evolution happen, just that it is not as likely as in the case of someone who has the IgVH unmutated variety of CLL. Clonal evolution is one reason to consider getting periodic FISH testing done, to see if you have become the ‘proud’ owner of a new chromosomal defect since the last time you looked.

I have a bunch of links below that might help you come up the learning curve, or refresh your memory if it has been a while. We have a lot of content on this website now. The best way to learn about CLL is to browse through the articles that catch your fancy, then use the live links we have embedded in each article to take you to new areas. It is a lot to take in one sitting, but persistence will pay off in better awareness of your own situation. If you think I am being a stern teacher here, and it takes too much effort to read all this stuff, just imagine how much time and effort it took me to research and write all this stuff in the first place. Believe me, getting this information from “Blood” or “Journal of Clinical Oncology” is a whole lot harder.

FISHing for Answers;
What Type of CLL Do You Have?;
What You and Your Oncologist Need To Know;
Prognosis at Diagnosis;
Clonal Evolution;
Dawn of a New Era.

Be well,

Chaya
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