CLL - Next Generation Sequencing

[Cave123]

I'm curious about Next Generation Sequencing for CLL. To my understanding, this type of test identifies resistant mutations, i.e., NOTCH1, ZAP-70, SF3B1, etc., and this can help your doctor to determine a targeted therapy that's more personalized. Not sure I have this correct so hopefully someone here can educate me on this. Has anyone here done this test and can you share your experience ? Thanks everyone, stay well, CAVE

[lankisterguy Volunteer]

Hi Cave123,

-

I've been part of several studies using NGS Next Generation Sequencing and had many discussions with my CLL expert doctor that is one of the leaders in this work.

If I recall the numerical data, when they compared the full sequences of 100 CLL patients with 100 non CLL patients, they found over 200 differences that appeared in the CLL patients but not in the others.

Notch 1, SF3B1, MYC, and several others were suspects that he thought might be indicators of complications like Richter's Transformation. But it's now 10 years after he started those investigations and only a few are still viable suspects, what the remainder affect is still unknown.

In the whole genome sequencing there are a significant portions that seem to be inactive and have no known purpose. The experts are still trying to figure out why those seem to be turned off.

Len

[Cave123 in reply to lankisterguy]

Hello lankisterguy, thanks for your response - what does MYC stand for ? Thanks again CAVE

[lankisterguy Volunteer in reply to Cave123]

I googled:

genetics Notch1 myc

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

pubmed.ncbi.nlm.nih.gov/281...

Len

[Kwenda]

My " Next Generation Sequencing " was done at a CLL research laboratory after they had confirmed the 13q del and mutated.

But they also commented " Whole chromosome monosomy - mitotic nondisjunction mosaicism ", but they were unable to comment on the effects of this on my CLL.

Basically there is much that remains unknown when you dig into CLL at this level, and it is unproven as to treatment choices or longevity.

Dick

[Cave123 in reply to Kwenda]

So....."Whole chromosome monosomy - mitotic nondisjunction mosaicism" was just something they noted but provided no helpful information about it (in terms of how this could affect you), if I understand you correctly? thanks CAVE

[Kwenda in reply to Cave123]

Like many things tested at this level it is unknown how this might affect our CLL. I don't believe it affects any treatment decisions.Dick

[Kwenda]

While into some deep investigations on CLL, this research was just published.

Study Uncovers Link Between Long Telomere Length, Cancer Predisposition

While there is a known link between shortened telomeres and age-related disease, excessively long telomere length may also have negative health implications, predisposing a person to a range of cancers, according to a new study in this week's New England Journal of Medicine.

The length of telomeres — which are made up of tandem sequences at chromosome ends that shorten with cell division — predicts the onset of replicative senescence and functions as a mitotic clock.

Short dysfunctional telomeres signal DNA damage, which elicits a cellular response that leads to senescence or apoptosis, and short telomere syndromes are associated with pulmonary and hematopoietic ( Blood Cells ) disease.

It is unclear, however, whether long telomere length is advantageous.

To investigate, a team led by Johns Hopkins University scientists examined the clinical and molecular features of aging and cancer in 17 people with heterozygous loss-of-function mutations in the telomere-related gene POT1, along with 21 relatives without the mutations.

They find that mutations that lead to long telomeres conferred a predisposition to a familial clonal hematopoiesis syndrome that was associated with a range of benign and malignant solid neoplasms.

"Overall, our data uncover an inherited cancer-predisposition mechanism that is distinct from that of mutations affecting tumor-suppressor proteins and oncoproteins: an extended cellular lifespan that supports clonal evolution with aging," they conclude.

genomeweb.com/scan/study-un...

nejm.org/doi/full/10.1056/N...

Dick

[SofiaDeo]

I had an NGS MRD test, to look for the number of CLL cells. They weren't looking for NOTCH-1 or other markers. NGS refers to the technology used, not exactly what is being tested.

oncology.labcorp.com/cancer...

thermofisher.com/us/en/home...

idtdna.com/pages/education/...

illumina.com/science/techno...

[Cave123]

Thank you SofiaDeo - those links contain good information I look forward to reviewing them. I was having a challenge finding good information online about this topic. In your opinion, in addition to NOTCH-1, what are some of the other common markers related to CLL, specifically, that might be helpful to know prior to selecting a treatment. For example, are there some markers that might be more resistant to a BTKi as opposed to a BCL-2 ? My doc does not feel that NGS testing is necessary b/c he feels that it would not change his decision about treatment when the time comes to select a treatment (I am treatment naive). He will support me and write me a referral to do the testing if I bring him the information (specific lab), but he will not tell me, or the lab, to my understanding, which specific markers to check for. I am also in the market for a lab that will send me a kit which I can have my blood drawn here in Toronto and then return it to them, and then they will send me and my doc the results - I heard this is how it's done. I think most of these labs are US based. Any additional insight is appreciated. Thanks SofiaDeo, stay well - CAVE

[SofiaDeo]

I don't think there's enough data to say yet whether one drug class works better against the various mutations like NOTCH-1. I am sure one of the reasons researchers are currently collecting these markers, is to try to determine this. The only thing I am aware of right now, is that doctors are discussing, if patients who have high risk factors for RT, should be treated sooner. If you tamp down the CLL before it can transform, will it actually help prevent the RT?