Can P53 occur or has it always been in your body?

[Ros123]

Are you born with P53 or does it just occur? I presume once it has happened it can't be cured and is just managed? Is it hereditary? If it does occur, without being there at birth, what are the causes? My hemotologist did explain but I'm afraid it just didn't sink in, any information would be appreciated.

[AussieNeil Partner Administrator]

Humans have 46 chromosomes in the DNA of each of our body cells; 23 from each of our parents. All CLL cells have some genetic damage - that's why they multiply faster than they die and our lymphocyte blood counts, nodes and bone marrow infiltration increase. (The quality checking process in the new cells which would normally trigger their destruction (managed by the Tumour Protein (TP53 or p53 gene) on the 17p chromosome in a process called apoptosis) is broken. The TP53 gene includes the recipe for making the p53 tumor suppressor protein and hence is deemed the guardian of the genome.)

In some of us, the CLL genetic damage is in the TP53 gene. That may have been the cause of the CLL developing from good B - lymphocytes, or it could have arisen from copying mistakes as the CLL cells keep dividing and growing, or more commonly arisen during chemotherapy treatment. This process is termed Clonal Evolution.

Because chemotherapy treatments like FCR rely on the CLL cells self destructing, which requires a functioning TP53 gene on the 17p chromosome, patients with p53/17p deletions don't have long remissions on these treatments and do much better on the newer, non-chemo treatments like Ibrutinib. This is why FISH testing is done prior to starting treatment in the UK and other countries; earlier testing may show an intact TP53 gene, but new CLL cells can arise with damage to that gene and become the dominant CLL clone. In your case, if you have this damage, I suspect your FCR treatment may have caused it, but we'll never know.

Neil

[Cllcanada Top Poster CURE Hero in reply to AussieNeil]

To clarify... TP53 mutation or non-function without 17p deletion does occur, and this is not seen on a FISH test result. It requires TP53 mutation analysis by Sanger or Next Generation Sequencing.

This is rare preformed clinically at the present time.

~chris

[artkula]

My father did not have del17p/TP53 before the first BR treatment. He responded to the treatment very well, but six month after the last chemo he suffered a relapse and had 45% cells with this mutation as measured from the node biopsy. No one knows why. Fortunately, with the new generation of Btk and Bcl-2 inhibitors, it is no longer the fatal mutation.

[Jm954 Administrator in reply to artkula]

There is a school of thought that says CLL is made up of many sub clones that are all present when we are first diagnosed.

Treatment affects the sub clones differently and clearance of some by treatment allows others, that may have not been detectable at the start of treatment, to grow and become more dominant.

[artkula in reply to Jm954]

Very interesting! I found this article, which indicates that TP53 status in subclones (undetectable by FISH but only highly sensitive ultra-deep-NGS) is equally bad for refractoriness as having clonal TP53 defects. The first-line therapy is based upon the TP53 status by FISH, and thus it may not always be adequate in case of having TP53 status in subclones.

bloodjournal.org/content/12...

[Cllcanada Top Poster CURE Hero in reply to artkula]

There is currently a project underway by ERIC to get at least one lab in CLL countries, certfied to do the advanced testing... but clinical use is a number of years away...

For now FISH is as good as it gets, clinically... with a few exceptions in major CLL Consortium Research hospitals...

All these can be tested for privately in the U.S. and occasional insurance companies will pay the costs, but it is quite rare...

CGI. does a great deal of genetics works for many clinical trials in the U.S.

cancergenetics.com/wp-conte...

~chris

[Ros123]

Thank you for all the replies. I think I had the FISH test at the start, before FCR and the test and was negative. I was just worried that this had been missed at that time. Now this test has come back with the mutated gene and although my hemotologist was very good at explaining it, because it was bad news about my scan and the various tumours, I didn't really take the information on board. Thank you all.

[Jm954 Administrator in reply to Ros123]

Do you think you might be having treatment soon?

Wishing you all the best.

[Ros123 in reply to Jm954]

Started Irbrutinib 2 weeks ago. So far so good apart free m chest infection.

[virdieblue]

Chris just posted a video on clonal evolution during treatment that is very informative. The doctor was from MD Anderson. Might help