Date: May 22, 2002
by Chaya Venkat
Blood cancers such as CLL are clonal diseases, that is, they are derived from a single cell in the bone marrow or peripheral lymph system that has undergone genetic mutation. A single mutation may cause no harm, and the mutated cell may die quickly because it fails to survive, or it may be given the apoptosis death signal and told to kill itself. But when the mutations accumulate, and they are of a particular kind that gives the cell a survival or growth advantage, then there is a good chance of cancer developing.
People, please do not confuse the genetic aberrations I am discussing here with the very necessary somatic mutation or IgVH gene mutation that I discussed in another article. Somatic mutation is a necessary function of B-lymphocytes, so that they can do their job of recognizing antigens and do their part in mounting an immune response.
The genes that are involved in the development of cancer fall into two broad groups: oncogenes that facilitate the survival and proliferation of cells, and tumor suppressor genes that are supposed to control cell death or apoptosis. In a "good" cell, these two forces of life and death are in equilibrium and the cell lives for only the right amount of time, and dies on queue, but not before its time. If the particular genetic mutation in a given cell increases the efficiency of an oncogene beyond what it should be, or decreases the function of a tumor suppressor gene, this important equilibrium is lost. The cell is now a cancer cell, in that it outlives its normal life span, and proliferates beyond the control of the body. You can see why that will cause trouble.
We all get one set of 22 chromosomes from each of our parents, plus one sex chromosome from each parent, for a total of 46. The chromosomes occur in pairs, numbered from 1 – 22 in decreasing size, and there is a pair of two XX chromosomes for females and XY chromosomes for males. 2 X 22 = 44, plus two sex chromosomes, that makes up the full set of 46 chromosomes. This state of affairs is called "diploid", or two chromosomes per pair.
When a cell divides to make a daughter, sometimes things go wrong. Instead of making an exact copy of the same 46 chromosomes that the mother cell had, the daughter cell may have gained an extra chromosome, or lost one of the set, or broken off a piece of one of the chromosomes, or a piece of one chromosome got broken off and got stuck in a wrong location. Normally, such a defective cell is not able to function and dies quickly, and that is the end of the story. But if the defect is such that actually helps the cell survive and thrive (an oncogene is empowered or over-expressed) and ignore the signal from the body to commit suicide (a tumor suppression gene is deleted), then cancer can initiate.
Each chromosome has two arms, the shorter is called "p" and the longer called "q". Each arm is further divided into regions numbered 1,2,3 etc. The four most common chromosome abnormalities in CLL are:
The reference below describes the study of 325 CLL patients. The results are tabulated here. The key statistic is overall survival time, in months.
|Mutation||Frequency||Effect||Overall Survival (months)|
|11q23||18%||Mutation of ATM gene||79|
|17p13||7%||Deletion of p53
As you can see, some mutations are more dangerous than others, and the worst of the lot is 17p13, which deletes the very important tumor suppressor gene, p53, on chromosome 17. For additional discussion of this topic, read the article titled The TP53 Gene.
In the case of four patients in this study, whose disease mutated and became much more aggressive after chemotherapy, in each case, the suddenly worsening prognosis was traced back to a new acquisition of p53 gene deletion, as an unfortunate consequence of therapy. We know that in a small percentage of cases, the very treatment that is supposed to cure us can cause further mutagenicity as a side effect. Here is an example of that happening, and the reason for it.
Interestingly enough, the high risk aberrations 17p13 and 11q23 (with overall survival of 32 months and 79 months respectively) were much, much more common in cases where the patients also showed unmutated IgVH gene mutation status, and high CD38 levels on their CLL cells.
So, now we can tie it all together: IgVH gene mutation status positive, low CD38 level on CLL cells, and absence of high risk genetic abnormalities such as 17p13 and 11q23, all of these are indicators of good prognosis, long treatment free life and overall survival.
It sounds reasonable to me that your therapy choices will be significantly influenced by your particular set of prognostic indicators. As I wrote in one of my earlier articles, if you are 50 plus years old, and you have all the "good" indicators, chances are higher you will die of old age (or get hit by a bus crossing the street) than due to CLL.
If on the other hand, you are IgVH gene unmutated, high CD38 levels, and you have deletion of the p53 tumor suppressor gene, don't spend too much time dithering, check out all the protocols open to you to hit the cancer hard, before the tumor burden grows too big. At the very least, get to a specialist hospital and not just your local oncologist to get a second opinion.
The problem is this: with the possible exception of CD38 levels, which some of the better equipped labs can do using quantitative flow cytometry, the other pieces of information, such as determination of IgVH gene mutation status and the identification of genetic aberrations are hard to perform. Only the most advanced cancer centers can do it in the first place, and unless you are a special patient enrolled in one of their clinical trials, they are not inclined to do it at all.
If there was one area of research that we can all get behind and try to advocate, I think it is this area of improved diagnostics. Chemotherapy is no fun, and causes a great deal of harm to the body, besides doing its job of killing cancer cells. I wonder how many CLL patients routinely undergo chemotherapy, when a better understanding of their prognosis would have made it clear that they can stay indefinitely in a watch and wait mode, with reasonable chance of a long and treatment-free life. Conversely, how many CLL patients die too soon, because they lulled themselves into a false sense of security by looking at general overall statistics that are not really applicable in their case, when their disease was unfortunately aggressive and needed to be treated aggressively?
New England Journal of Medicine, Volume 343:1910-1916 December 28, 2000 Number 26
Genomic Aberrations and Survival in Chronic Lymphocytic Leukemia
Hartmut Döhner, M.D., Stephan Stilgenbauer, M.D., Axel Benner, M.Sc., Elke Leupolt, M.D., Alexander Kröber, M.D., Lars Bullinger, M.D., Konstanze Döhner, M.D., Martin Bentz, M.D., and Peter Lichter, Ph.D.
Background Fluorescence in situ hybridization has improved the detection of genomic aberrations in chronic lymphocytic leukemia. We used this method to identify chromosomal abnormalities in patients with chronic lymphocytic leukemia and assessed their prognostic implications.
Methods Mononuclear cells from the blood of 325 patients with chronic lymphocytic leukemia were analyzed by fluorescence in situ hybridization for deletions in chromosome bands 6q21, 11q22–23, 13q14, and 17p13; trisomy of bands 3q26, 8q24, and 12q13; and translocations involving band 14q32. Molecular cytogenetic data were correlated with clinical findings.
Results Chromosomal aberrations were detected in 268 of 325 cases (82 percent). The most frequent changes were a deletion in 13q (55 percent), a deletion in 11q (18 percent), trisomy of 12q (16 percent), a deletion in 17p (7 percent), and a deletion in 6q (6 percent). Five categories were defined with a statistical model: 17p deletion, 11q deletion, 12q trisomy, normal karyotype, and 13q deletion as the sole abnormality; the median survival times for patients in these groups were 32, 79, 114, 111, and 133 months, respectively. Patients in the 17p- and 11q-deletion groups had more advanced disease than those in the other three groups. Patients with 17p deletions had the shortest median treatment-free interval (9 months), and those with 13q deletions had the longest (92 months). In multivariate analysis, the presence or absence of a 17p deletion, the presence or absence of an 11q deletion, age, Binet stage, the serum lactate dehydrogenase level, and the white-cell count gave significant prognostic information.
Conclusions Genomic aberrations in chronic lymphocytic leukemia are important independent predictors of disease progression and survival. These findings have implications for the design of risk-adapted treatment strategies.
GENOMIC ABERRATIONS, p53 ABNORMALITIES, AND IgV MUTATION STATUS: RELATION TO DISEASE EVOLUTION, RESISTANCE TO THERAPY AND CLINICAL COURSE OF CLL
S. Stilgenbauer, L. Bullinger, A. Kröber, A. Benner, P. Lichter, H. Döhner.
Department of Internal Medicine III, University of Ulm, and DKFZ, Heidelberg, Germany.
Summary of important findings from the University of Ulm and Deutsches Krebsforschungszentrum, the German Cancer Research Foundation.
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Topic: Disease Characteristics