TP53 testing

[Mcc28]

Hi there,

I have just started treatment with V and O. Went to a CLL specialist before treatment began and he asked if I had TP53 sequencing/dissected (different than FISH). I went back to my hematologist and asked about the TP53 sequencing and he said yes it was done and sent me the fish results again.

I have an appointment soon with my hematologist and I’d like to better understand the TP53 sequencing the CLL specialist was referring to.

It seems to me people talk about IGVH and fish . Is there another gene sequencing test?

Thank you!

[SofiaDeo]

There's evidence that the type/position of various mutations in the TP53 gene are of clinical significance, and may be used in some treatment decisions. So there is a growing body of evidence that more specific testing within TP53 has meaning, instead of a yes-no "is there a TP53 mutation". Some TP53 mutations appear to contribute to adverse outcomes more than others.

medlineplus.gov/lab-tests/t...

pubmed.ncbi.nlm.nih.gov/305...

nature.com/articles/s41418-...

nature.com/articles/s41598-...

There's a large database being built that characterizes if a TP53 mutation is associated with a cancer, what type of cancer, exactly how it contributes to the cancer, and other information.

dceg.cancer.gov/tools/publi...

[Mcc28 in reply to SofiaDeo]

Thank you so much. What is the TP53 test called? I want to be sure to ask for the right test.

Thank you for detailed response and time you took. Really appreciated

[SofiaDeo in reply to Mcc28]

I have no way of knowing what the test in your part of the world is called. There's nothing in your profile, I can't even hazard a guess. If you Google the lab company your doctor uses, they may list it if you search their offerings. In the US, Qwest is a common provider (there are others) and the test appears as this:

testdirectory.questdiagnost...

[lankisterguy Volunteer in reply to Mcc28]

Hi Mcc28,

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I suspect that NGS (Next Generation Sequencing) may be the current method of testing see: frontiersin.org/journals/on... but that may be expensive, and only required to differentiate low levels and mutations vs >10% deletions of TP53.

Many health insurance organizations may balk at paying for the really exotic tests, since they prefer tests that have proven clinical significance or are needed to choose specific drugs for treatment.

The TP53 studies to date seem to be more "bleeding edge" research and not essential for choosing from the current targeted treatments for CLL (as long as Chemo is not on the table).

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Len

[Skyshark in reply to lankisterguy]

In June CLL14 trial Of V+O changed the story, "Patients with MRD ≥10-4 after Ven-Obi have a shorter OS than patients with MRD <10-4, highlighting the need for dedicated MRD-guided approaches."

medically.gene.com/global/e...

There are different types of NGS tests. UK NHS pays under £400 for a NGS test that will detect uMRD4. Testing for uMRD6 by CloneSEQ is around £1400 in UK and is being piloted at Sheffield. CloneSEQ is the standard used for clinical trials but cheaper uMRD4 is all that's needed to determine if V should continue after 12 cycles of V+O.

I can see from doctors letters to my GP that I've had a NGS test. FISH can detect TP53 deletion but not mutation.

"Bone marrow shows heavy infiltration (at least 75%) with B cells positive for CD20, CD79a, BCL2, CD 23 and low Ki67 (in keeping with atypical CLL)

Interphase FISH shows deletion of ATM but no TP53 deletion.

NGS panel shows variant in SF3B1 with no other significant variant in other genes including TP53."

[SofiaDeo in reply to lankisterguy]

NGS isn't a specific test for the*type* of TP53 mutation, it's a technology. The article you referenced is talking about NGS being used to count the number of TP53 mutations and their clinical significance in CIT therapy patients, but it isn't the test to determine exactly where on the TP53 allele the mutation occurs. Since some TP53 mutations do not appear to be linked to certain cancers, while others are, the database was started. I take this question to mean "what is the test to tell me exactly where the mutations are" and that the regular hematologist misunderstood what the CLL specialist was asking for, since the hematologist referred back to the FISH results. FISH can tell if one has abnormalities in TP53; the test I referenced is used to determine exactly where on TP53 the mutations are. NGS can be used for both, there are specific tests that just happen to use NGS technology to supply different types of data. Much like uMRD testing can use flow cytometry or NGS technology to answer "is there CLL present in this sample".

[Skyshark in reply to SofiaDeo]

CLL14 trial has 25 subjects with TP53del/mut. When TP53del/mut is combined with IgHV status it has 16 IgHVunm and 5 IgHVmut.

CAPTIVATE has 29 with TP53 del/mut. With IgHV status it's 17 IgHVunm and 12 IgHVmut.

IgHVmut with TP53del/mut do far better than IgHVunm. Splitting them into 2 sets results in worse outcome for IgHVunm and better for the IgHVmut set. CLL14 median for all TP53del/mut is 51.9 months, for IgHVunm+TP53del/mut it is reduced to 47 months, while for IgHVmut+TP53del/mut the median hasn't been reached.

The small numbers means the results have poor confidence intervals. Any attempt to split the TP35del/mut into smaller sets will require much larger cohorts on trials and/or very long recruitment times to get enough people on the study with the required subset mutation.

[lankisterguy Volunteer]

Hi Mcc28,

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Adding to the excellent reply & links by SofiaDeo , see this ncbi.nlm.nih.gov/pmc/articl...

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Some data for TP53 deletions and 17p deletions show they are often related, and indicate that Chemo therapy was ineffective for patients with either. More recent studies show that with the modern targeted therapies, mutated TP53 is better than dual deleted TP53.

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

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Len

[Mcc28 in reply to lankisterguy]

Thanks Len, much appreciated.

[avzuclav]

To answer your question, yes, it is a different test (not FISH).

"For patients with chronic lymphocytic leukemia (CLL), TP53 sequencing, in addition to FISH for 17p deletion, aids in prognosis and/or therapy selection. "

neogenomics.com/test-menu/t...