Trying to Interpret FISH results: Last year... - CLL Support

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Trying to Interpret FISH results

The-Man-with-a-Plan profile image

Last year, when I met my hematologist for the first time, he told me my CLL was indolent. W/W is where things stand. Looking at the information below, one would think I'm 'normal'. I know I'm not. I have CLL. Anyway, what the heck does the info below really mean? I am 65 yo male and IgHV unmutated. Thanks for any/all feedback.

CLL, FISH

: Result Summary - Normal

Interpretation

: The result is within normal limits for the CLL FISH panel and the CCND1 and IGH gene regions.

Result Table

----------------------------------------------------------

Abnormality Name Result Abn Cutoff (%)

(%)

-6q23(D6Z1x2,MYBx1) Normal <4.0

-11q22.3(D11Z1x2,ATMx1) Normal <7.5

+12(D12Z3,MDM2)x3 Normal <2.5

-13q14.3(D13S319x1,LAMP1x2) Normal <7.0

-13q14.3x2(D13S319x0,LAMP1x2) Normal <1.5

t(11;14) CCND1-XT/IGH-XT fusion Normal <0.6

-17p13.1(TP53x1,D17Z1x2) Normal <9.5

-17(TP53,D17Z1)x1 Normal <5.5

----------------------------------------------------------

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The-Man-with-a-Plan profile image
The-Man-with-a-Plan
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13 Replies
cajunjeff profile image
cajunjeff

Cll is caused by a chromosome abnormality. FISH looks for the most common abnormalities. Your FISH test looked at the regions of chromosomes 6, 11, 12,13 and 17 where some missing or added genetic material is usually found with cll. Your FISH test was normal, meaning you do not have one of the typical chromosomal abnormalities.

A normal FISH does not mean you do not have a defect somewhere in some chromosome. You have cll so you almost certainly have a chromosomal defect. So why doesn't FISH look at every region of every chromosome? I think that is because that would be an enormously expensive and time consuming thing to do. Gardening Girl might could better explain what would be involved in looking at that. We have 25000 genes in our chromosomes, FISH just looks at a handful of them.

People with cll and a normal FISH are thought to have an intermediate prognosis, not as good as 13q deleted alone, but better than 17p deleted.

Here is a better explanation than mine:

clltopics.org/PI/Murky.html

The-Man-with-a-Plan profile image
The-Man-with-a-Plan in reply tocajunjeff

Thanks Cajun Jeff! You always have very helpful and insightful answers.

cajunjeff profile image
cajunjeff in reply toThe-Man-with-a-Plan

You are very welcome. I might add that how our cll actually does is way more important than what our markers predict it will do. Its hard to put "normal" FISH results into any risk bucket because the area of the defect is unknown.

Your doctor has described your cll as indolent, meaning to me that he is observing that your cll progresses slowly. To me, the fact your cll actually acts in an indolent way is the most important predictor.

gardening-girl profile image
gardening-girl in reply tocajunjeff

Great link Jeff, to Chaya's discussion of the FISH test. As both you and Chaya point out the typical CLL FISH panel only looks at major chromosomal deletions, additions or rearrangements. To look for teeny, tiny defects in genes & chromosomes, for example, single nucleotide base changes that can profoundly alter gene or protein function, DNA has to be sequenced.

Most of the DNA sequencing for CLL outside clinical trials targets a few genes that have been shown to have prognostic significance, for example sequencing ATM, BIRC3, NOTCH1, SF3B1, and TP53 genes.

The link below is an interesting discussion of CLL Diagnostics: Next-Generation Sequencing (NGS) of TP53

medpagetoday.com/resource-c...

For academic studies of CLL, companies such as Genoptix offer a CLL Comprehensive Panel that sequences parts of about 50 genes by NGS technology. There have also been whole genome sequencing (WGS) and whole exon sequencing (WES) studies done on CLL cells, but this is quite rare and generates massive amounts of data.

cajunjeff profile image
cajunjeff in reply togardening-girl

Good stuff GG. The term "sequencing" is confusing to me and others, but I get the gist.

In the context of this discussion, a FISH test picks out five or so genes to look at and they know where the genes are located at on our chromosomes to find them.

GG, it appears that in the "man with a plan's" case, all these five genes were normal. So if we wanted to go fishing to find what gene he had that was damaged to create his cll, would one have to look at thousands upon thousands of genes to find it?

How long would it take to "sequence" thousands of genes? What would the cost be? Can you simply the term "sequence a gene" and what it means in layman's terms?

I think some people with a so called "normal" FISH test can be confused as to why their abnormal chromosome/gene cannot be discovered.

gardening-girl profile image
gardening-girl in reply tocajunjeff

Jeff, the short answer to your question about DNA sequencing is that sequencing DNA simply means determining the order of As, Ts, Cs and Gs in a stretch of DNA.

Clinical whole-exome sequencing that sequences only the genes that are being expressed at any given time costs maybe $500, and whole-genome sequencing could cost maybe $1000. The actually sequencing is fast..a day or two, but if cells have to be grown in culture first, it can be days before the sequencing is done.

Then of course there is always the problem of analyzing the data! As far as I know, no one knows what specific mutations cause CLL. As you know there are the mutations to which I referred above (ATM, BIRC3, NOTCH1, SF3B1, and TP53 ) that could provide prognostic information and those, especially the TP53 mutation should be sequenced before any treatment decision is made.

I am going to use the p53 gene as an example of what a DNA sequence looks like with the As, Ts, Cs & Gs representing the four nucleotides that make up DNA, and then I’ll highlight the most frequent p53 mutation in CLL.

First I need to define a codon. A codon is a three nucleotide sequence that specifies a particular amino acid. In the sequence below, codon 1, the sequence of which is ATG (underlined below), codes for the amino acid methionine (M) and Codon 2, GAG, codes for glutamic acid (E), ETC!

In p53 there are six ‘hotspot’ codons (175, 245, 248, 249, 273, and 282) associated with CLL.

ncbi.nlm.nih.gov/pmc/articl...

I’ll use codon 175 as an example:

Because of a single base change from guanine (G) to adenine (A) in the p53 gene at codon 175, the amino acid histidine (H) replaces the amino acid arginine (R) in the resulting TP53 protein. That causes the shape of the protein to change, interfering with its ability to bind to DNA and guard the genome.

Nucleotide Sequence of the human p53 gene (1182 nucleotides long) with codon 175 marked as

CGC° Can you find it?

1ATGGAGGAGCCGCAGTCAGATCCTAGCGTCGAGCCCCCTCTGAGTCAGGAAACATTTTCAGACCTATGGAAACTACTTCCTGAAAACAACGTTCTGTCCCCCTTGCCGTCCCAAGCAATGGATGATTTGATGCTGTCCCCGGACGATATTGAACAATGGTTCACTGAAGACCCAGGTCCAGATGAAGCTCCCAGAATGCCAGAGGCTGCTCCCCCCGTGGCCCCTGCACCAGCAGCTCCTACACCGGCGGCCCCTGCACCAGCCCCCTCCTGGCCCCTGTCATCTTCTGTCCCTTCCCAGAAAACCTACCAGGGCAGCTACGGTTTCCGTCTGGGCTTCTTGCATTCTGGGACAGCCAAGTCTGTGACTTGCACGTACTCCCCTGCCCTCAACAAGATGTTTTGCCAACTGGCCAAGACCTGCCCTGTGCAGCTGTGGGTTGATTCCACACCCCCGCCCGGCACCCGCGTCCGCGCCATGGCCATCTACAAGCAGTCACAGCACATGACGGAGGTTGTGAGGCGC°TGCCCCCACCATGAGCGCTGCTCAGATAGCGATGGTCTGGCCCCTCCTCAGCATCTTATCCGAGTGGAAGGAAATTTGCGTGTGGAGTATTTGGATGACAGAAACACTTTTCGACATAGTGTGGTGGTGCCCTATGAGCCGCCTGAGGTTGGCTCTGACTGTACCACCATCCACTACAACTACATGTGTAACAGTTCCTGCATGGGCGGCATGAACCGGAGGCCCATCCTCACCATCATCACACTGGAAGACTCCAGTGGTAATCTACTGGGACGGAACAGCTTTGAGGTGCGTGTTTGTGCCTGTCCTGGGAGAGACCGGCGCACAGAGGAAGAGAATCTCCGCAAGAAAGGGGAGCCTCACCACGAGCTGCCCCCAGGGAGCACTAAGCGAGCACTGCCCAACAACACCAGCTCCTCTCCCCAGCCAAAGAAGAAACCACTGGATGGAGAATATTTCACCCTTCAGATCCGTGGGCGTGAGCGCTTCGAGATGTTCCGAGAGCTGAATGAGGCCTTGGAACTCAAGGATGCCCAGGCTGGGAAGGAGCCAGGGGGGAGCAGGGCTCACTCCAGCCACCTGAAGTCCAAAAAGGGTCAGTCTACCTCCCGCCATAAAAAACTCATGTTCAAGACAGAAGGGCCTGACTCAGACTGA

1182

CGC codes for the amino acid arginine (R)

Transcription and Translation of the p53 gene results in the 393 amino acid TP53 protein with the 175th amino acid R marked as R°

MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGPDEAPRMPEAAPPVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTAKSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRCPHHERCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNYMCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPHHELPPGSTKRALPNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAGKEPGGSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD

Nucleotide Sequence of the gene coding for the 175 R>H mutant p53 (1182 nt):

CGC°CAC°

ATGGAGGAGCCGCAGTCAGATCCTAGCGTCGAGCCCCCTCTGAGTCAGGAAACATTTTCAGACCTATGGAAACTACTTCCTGAAAACAACGTTCTGTCCCCCTTGCCGTCCCAAGCAATGGATGATTTGATGCTGTCCCCGGACGATATTGAACAATGGTTCACTGAAGACCCAGGTCCAGATGAAGCTCCCAGAATGCCAGAGGCTGCTCCCCCCGTGGCCCCTGCACCAGCAGCTCCTACACCGGCGGCCCCTGCACCAGCCCCCTCCTGGCCCCTGTCATCTTCTGTCCCTTCCCAGAAAACCTACCAGGGCAGCTACGGTTTCCGTCTGGGCTTCTTGCATTCTGGGACAGCCAAGTCTGTGACTTGCACGTACTCCCCTGCCCTCAACAAGATGTTTTGCCAACTGGCCAAGACCTGCCCTGTGCAGCTGTGGGTTGATTCCACACCCCCGCCCGGCACCCGCGTCCGCGCCATGGCCATCTACAAGCAGTCACAGCACATGACGGAGGTTGTGAGGCAC°TGCCCCCACCATGAGCGCTGCTCAGATAGCGATGGTCTGGCCCCTCCTCAGCATCTTATCCGAGTGGAAGGAAATTTGCGTGTGGAGTATTTGGATGACAGAAACACTTTTCGACATAGTGTGGTGGTGCCCTATGAGCCGCCTGAGGTTGGCTCTGACTGTACCACCATCCACTACAACTACATGTGTAACAGTTCCTGCATGGGCGGCATGAACCGGAGGCCCATCCTCACCATCATCACACTGGAAGACTCCAGTGGTAATCTACTGGGACGGAACAGCTTTGAGGTGCGTGTTTGTGCCTGTCCTGGGAGAGACCGGCGCACAGAGGAAGAGAATCTCCGCAAGAAAGGGGAGCCTCACCACGAGCTGCCCCCAGGGAGCACTAAGCGAGCACTGCCCAACAACACCAGCTCCTCTCCCCAGCCAAAGAAGAAACCACTGGATGGAGAATATTTCACCCTTCAGATCCGTGGGCGTGAGCGCTTCGAGATGTTCCGAGAGCTGAATGAGGCCTTGGAACTCAAGGATGCCCAGGCTGGGAAGGAGCCAGGGGGGAGCAGGGCTCACTCCAGCCACCTGAAGTCCAAAAAGGGTCAGTCTACCTCCCGCCATAAAAAACTCATGTTCAAGACAGAAGGGCCTGACTCAGACTGA

CAC° codes for the amino acid histidine (H)

which has taken the place of arginine (A) in this mutant TP53

Transcription and Translation of the mutant p53 gene results in the 393 aa mutant TP53 protein (393 aa):

MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGPDEAPRMPEAAPPVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTAKSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRH°CPHHERCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNYMCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPHHELPPGSTKRALPNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAGKEPGGSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD

Summary: Codon 175 CGC of the p53 gene mutates to CAC causing a single amino acid change (R>H) in TP53 protein interfering with its normal activity.

ncbi.nlm.nih.gov/projects/C...

To gain a basic understanding of DNA, RNA and proteins, and the processes by which information in genes is translated into proteins, I highly recommend this site:

ib.bioninja.com.au/standard...

When I composed this message I had things highlighted with color, but unfortunately the color all disappeared when I cut and pasted the text. 😩

Smakwater profile image
Smakwater in reply togardening-girl

Slightly above reseting stuck brushes on a volkswagen starter!

I am going to go ice my cranium, and save some of the fun for later.💆‍♂️

JM

The-Man-with-a-Plan profile image
The-Man-with-a-Plan in reply togardening-girl

Gardening Girl

Dr. Furman did order a Genoptix panel. I looked at the results 3-4 different times. Honestly, it's all Greek to me. Waaaay too much data for this CLL neophyte. He and I have never discussed the results. (Honestly, I'm lucky if I talk to him for 20-30 minutes every 6 months.) Perhaps my genetic signature has scientific value. During my first visit back in 2019, I agreed to participate in any/all Weill Cornell/NY Presbyterian CLL studies.

Anyway, thanks for your in-depth feedback. Having you and Cajun Jeff as my CLL 'consultants' is a real bonus. :)

gardening-girl profile image
gardening-girl in reply toThe-Man-with-a-Plan

Hey Man, don't ever hesitate to ask questions. I learn so much from questions as well as answers!

cajunjeff profile image
cajunjeff in reply toThe-Man-with-a-Plan

Come on man with the plan, what about MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPG is so hard understand? :)

I would probably have switched the WFT sequence GG wrote above to WTF, but I dont want to second guess her. LOL.

Thanks for mentioning me with GG, but I just do not understand these things on the same level she does.

The-Man-with-a-Plan profile image
The-Man-with-a-Plan in reply tocajunjeff

THE QUICK BROWN FOX JUMPED OVER THE LAZY DOG! There, I just covered the entire English Alphabet.

CG covered the entire human genome alphabet!

We're both good to go.

Now, I've got to get back to switching out my car's FTL drive train.

BTW, I did LOL when I read your comments. You're a very funny guy!

gardening-girl profile image
gardening-girl in reply toThe-Man-with-a-Plan

No! No! You forgot the As & Ts! ATC&G cover the entire genome alphabet.

Isn't it totally amazing that just by rearranging those four nucleotides, more than 20,000 different cellular proteins can be produced? 🤔

gardening-girl profile image
gardening-girl in reply tocajunjeff

Now Jeff, it's just not nice to mess with the p53 gene sequence that way! 😉

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