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Double Trouble : More is Not Better When it Comes to 13q Deletions

Date: October 9, 2024

One of the reasons why "Harvey" was anxious to get moving with the stem cell transplant earlier this year was that his FISH test results showed ever increasing chromosomal mutations, deletions and errors in his CLL cells. Some of these mutations and deletions were so strange that no one had a clue what they meant. Mangling of the chromosomes in this way is often labeled “cryptic”, a fancy word for saying the experts have no clue what it means, but it is a sure indication his CLL cells were becoming ever more unstable and dangerous. My imagery is that of a wounded tiger, a more unpredictable and dangerous animal. FISH test results are hard to read and understand, especially if you slept through your high school biology class, here is a quick (and I promise you, painless!) refresher.

Normal human cells have 46 chromosomes: 22 pairs of chromosomes numbered 1-22 and two sex chromosomes (women have two “x” sex chromosomes, while men have one each of “x” and “y” sex chromosomes). (22 X 2) + 2 sex chromosomes = a total of 46 chromosomes. Of particular interest to CLL patients are chromosomes #13, #12, #11 and #17. In this particular cancer patients can have bits broken off (“deleted”) on chromosomes 13, 11 or 17. In the case of chromosome #12, CLL patients often have three copies of the chromosome, rather than the pair (2 copies) that are supposed to be there. This is called 12 Trisomy. (Trisomy means 3 copies).

Under the microscope chromosomes appear as thin, thread-like structures. They all have a short arm and long arm separated by what looks like a crimped in waist, called the centromere. The short arm is designated as p and the long arm as q. So, when we say a patient has 13q14.3 deletion, we are saying chromosome #13 has sustained damage and the zip-code for the exact location where the bit broke off on the long arm (“q”) of the 13th chromosome is provided by the designation 14.3. Put it all together, and we can now understand the designation “del 13q14.3”.

The FISH probe used to look for this particular bit of the 13th chromosome is called “D13S319”. Don’t let the jargon flummox you, D13S319 is just another name – we could just easily have called it “Daisy” for example. Moving along, the probe looks to see if there are two 13q14.3 bits present. In a healthy cell there should be two such bits, one on each of the pair of chromosome #13. The result for a healthy cell would therefore read as 13q14.3(D13S319X2). In plain English, the D13S319 probe looked and found 2 of the 14.3 bits, one each on the long “q” arm of the pair of chromosome #13, exactly as it should on a healthy cell.

How would the FISH test report read if the q14.3 bits has broken off on 1 of the 13th chromosome, but the other one of the pair is still OK? The report would say “13q14.3(D13S319X1)”. The “1” (highlighted in red for your convenience) says that the probe looked and found only 1 of the 13q14.3 bits. The second one has gone missing in action, an indication of chromosomal damage. Each member of a pair of chromosomes is called an allele, and 13q14.3(D13S319X1) is therefore called a mono-allele deletion.

If you are a newly diagnosed CLL patient and your first FISH test showed that you had 13q14.3(D13S319X1), a single deletion on one of the pair of chromosome #13, you can heave a sigh of relief. This is known to be the least dangerous of the various chromosome defects CLL patients can have. Even with one of the 13q14.3 pieces missing, the other intact member of the pair of chromosome #13 can still do what it has to do, more or less, and that is good news.

What if both of the 13q14.3 bits are damaged? What if the damage is not limited to just one of the pair, what if both of the 13th chromosomes took the same hit, shedding the exact same piece of themselves? In other words, what if the FISH report said the probe saw no 13q14.3 bits and a bi-allele deletion was observed, reported as 13q14.3(D13S319X0) ? Does this mean double trouble?

Intuitively, I think most of us would arrive at the right conclusion, that deletion of both of the 13q14.3 bits is not good news. For starters it suggests the CLL cells are continuing to evolve, getting more and more mangled over time – a case of clonal evolution to more dangerous state. Double (bi-allele) deletions of 13q14.3 are worse than mere single (mon-allele) deletions, since it is worse when both members of the pair are damaged. The abstract below confirms our layperson guess.

I hope I have given you a bit of a handle on how to read FISH reports. Different labs have different ways of reporting results, which can make things confusion. For example the abstract below uses 13q14x2 for bi-allele deletion and 13q14x1 mono-allele deletion. Feel free to write if you have questions. Here are a few links to get you started learning more about the FISH test and why it is important in determining your CLL prognosis.

• FISHing in Murky Waters
• FISHing for Answers
• What Type of CLL Do You Have?

Be well,
Chaya

Eur J Haematol. 2024 May 6.

Biallelic deletion 13q14.3 in patients with chronic lymphocytic leukemia. Cytogenetic, FISH and clinical studies.

Chena C, Avalos JS, Bezares RF, Arrossagaray G, Turdó K, Bistmans A, Slavutsky I.

Departamento de Genética, Instituto de Investigaciones Hematológicas “Mariano R.Castex”, Academia Nacional de Medicina, Buenos Aires, Argentina.

Background and objective: Monoallelic deletion of 13q14.3 (13q14x1) is the most common abnormality in chronic lymphocytic leukemia (CLL). As a sole alteration, it predicts a favorable outcome. Biallelic 13q14.3 (13q14x2) deletion or concomitant 13q14x1/13q14x2 has been scarcely evaluated in the literature. We present the clinical, cytogenetic and FISH analysis of six CLL patients with normal karyotypes and 13q14x2 and their comparison to cases with 13q14x1 as a single abnormality. Patients and methods: A total of 103 CLL patients were studied. Cytogenetic and FISH analysis were performed on stimulated peripheral blood lymphocytes. Specific fluorescence DNA probes for CLL were used. Results: Six out of 103 (5.8%) patients showed normal karyotypes and 13q14x2. It was observed as a single alteration in one patient and combined with 13q14x1 in 5 cases. Biallelic clones were larger than monoallelic ones in 3/5 patients (60%). The comparison of clinical and hematological data between 13q14x1 and 13q14x2 groups showed progression of the disease in all 13q14x2 patients respect to 12/32 (37.5%) cases with 13q14x1 (p=0.008), significant differences in the distribution by Rai stage (p=0.042) and a tendency of a higher LDH level in 13q14x2 patients (p=0.054). Treatment free-survival for 13q14x2 (biallele deletion ) group was 28.5 months, shorter than those observed in patients with 13q14x1 (monoallele deletion) alone (49 months). Conclusions: Our data would suggest that 13q14x2 could represent a more aggressive FISH anomaly than 13q14x1 alone, probably as a consequence of clonal evolution and/or due to the complete inactivation of this critical region by mean of more complex mechanisms.

PMID: 18462257 [PubMed - as supplied by publisher]

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