Optical Genome Mapping: a promising new tool to assess genomic complexity - Part Two

[bennevisplace]

Further to healthunlocked.com/cllsuppo...

An update from watching the OGM webinar

My impression is that AML cells' DNA has greater structural variation (mutation) than seen in CLL. Some of the combinations of deletion/ duplication/ insertion/ translocation described in AML were mind-boggling, and occasionally there occur "cryptic" translocations, invisible to FISH, nevertheless clinically significant. OGM can achieve 20 to 100 times the resolution of other analytical methods.

That said, it seems likely that when OGM is routinely applied to CLL, genomic variations will be discovered that were not apparent before, enabling certain "complex karyotypes" to be better understood and new prognostic markers to be identified. We have a glimpse of this already in the recent paper ncbi.nlm.nih.gov/pmc/articl... and the earlier ashpublications.org/blood/a...

The OGM workflow is straightforward compared with karyotyping plus FISH/ NGS etc. The claim that OGM "could potentially replace current cytogenomic methodologies" (see abstract above) was not made in the webinar. It was more a case of: we know OGM excels at certain things, it doesn't excel at everything, how can we use it alongside other methods? An international working group has been set up to to examine this question, whiich is also considered in a recent Special Report in Blood journal ashpublications.org/blood/a...

Wider applications of Optical Genome Mapping

OGM has been used to identify rare genetic mutations (the non-pejorative term is structural variations) that may pre-dispose people to progressing to severe Covid19 sciencedirect.com/science/a...

OGM for the chromosomal characterization of cell lines used in preclinical and clinical research aacrjournals.org/cancerres/...

A clinical trial to detect genomic structural variants in human DNA by OGM compared to prior clinical genetic tests such as chromosomal microarray analysis (CMA), karyotyping, Southern blot analysis, polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), and/or next generation sequencing (NGS), etc. in 1,000 individuals with an identified genomic abberration clinicaltrials.gov/ct2/show...

[Snakejaw]

Fascinating, as someone with “normal” karyotype cll, I’m curious if OGM could be used to determine what exactly is going on with my dna. While the normal label feels reassuring, it’s lacking information that could be helpful for predicting disease progression (I think). Thanks for posting this, hopefully we can get more advanced prognostic info in the future.

[bennevisplace in reply to Snakejaw]

Based on what I've read, OGM has the potential to map genomic variation in "normal karyotype" and perhaps develop new prognostic markers. I don't know how far away we are from this being common practice in CLL.

[Snakejaw in reply to bennevisplace]

Seems like I’m usually looking to the future 🙂. Cheers!

[AussieNeil Partner Administrator in reply to bennevisplace]

Promising practical research bennevisplace. Applying this or other similar technology to CLL could revolutionise the development of truly personalised treatment.

With respect to your comment above that "occasionally there occur "cryptic" translocations, invisible to FISH". It's actually more often than occasionally with the CLL FISH test - it's about 1 in 5 of us!

Per the abstract introduction of ashpublications.org/blood/a...

with my emphasis:-

It is well established that genetic prognostication using fluorescence in situ hybridization (FISH) for the common recurrent abnormalities deletion 13q, trisomy 12, deletion 11q, and deletion 17p hierarchically stratifies time to first treatment (TTFT) and overall survival (OS) for chronic lymphocytic leukemia (CLL) patients (pts). Approximately 20% of CLL pts are negative for each of these abnormalities (normal 12/13/11/17), which is considered a favorable prognostic finding. Although favorable, outcomes within this group are heterogeneous, with limited information as to the importance of other simultaneous factors.

I'm 'normal karyotype' yet I developed CLL and per the above, about 20% of us fall into this category, which is due to deletions/ duplications/ insertions/translocations not checked by standard FISH testing. Given the above, I'm not sure whether "AML cells' DNA has greater structural variation (mutation) than seen in CLL".

Neil

[CLLerinOz Administrator in reply to AussieNeil]

The project that is creating a new molecular map of CLL also suggests that the genetic complexity of CLl is much more diverse than we previously thought.

". . . the genetic and biologic landscape of CLL is more complex than previously appreciated." (Gad Getz, PhD Director of Bioinformatics, Mass General Cancer Center)"

'The scientists identified 202 genes (109 of which were novel) that when mutated could potentially drive CLL, and they refined the characterization of subtypes of CLL with distinct genomic characteristics and prognoses. Beyond genetic sequences, the expression patterns of certain genes further subcategorized CLL and provided valuable prognostic information.'

healthunlocked.com/cllsuppo...

[bennevisplace in reply to CLLerinOz]

Thanks for the heads up and this great reference. I missed this when you posted it. Have now fixed that issue!

[bennevisplace in reply to AussieNeil]

Thanks for those insights Neil.

On your last point, I'm not sure either. The webinar gave me the impression that, compared to CLL, AML can give rise to a much more complex mutational landscape. Is this associated with greater genomic instability in acute leukaemias, or is the impression due to CLL being less well studied?

[AussieNeil Partner Administrator in reply to bennevisplace]

AML is an acute leukaemia of the myeloid stem cell line, from which we get red blood cells, platelets and all the white blood cells except for lymphocytes, which come from the lymphoid line. That could explain a more complex mutational landscape for AML, but I'll leave it to researchers familiar with both blood cancers to weigh in on which has the more complex mutational landscape.

The US statistics for both have similar median ages at diagnosis and new cases per year of 68 and 20,050 for AML vs 70 and 20,160 for CLL originalText

originalText

We have a huge advantage in 5 year survival rate of 87.9% vs 30. 5%

What staggers me is that for CLL, we still don't definitely know the mechanism by which we get two groups of people of roughly the same size with historically different outcomes; IGHV mutated vs unmutated. Does the degree of mutation show the maturity of the B cell progenitor, or is it measure of how badly damaged the B cell's repair mechanisms are?

Neil

[bennevisplace in reply to AussieNeil]

Yeah of course, I hadn't factored in the stem cell difference. When you consider that, it's astonishing that the new case rates for CLL and AML are virtually the same.

Re the IGHV question, I take it you're talking just CLL now, because you have posed it before. I have no idea what the answer is.

[bennevisplace]

LATEST: OGM WEBINAR NOW AVAILABLE ON DEMAND

The Optical Genome Mapping webinar, in which Dr. Adam Smith describes how his organization has evaluated optical genome mapping as a first-line test for hematologic malignancies, focusing on acute myeloid leukemia.is available at workcast.com/ControlUsher.a...

This is cutting edge stuff, with very practical implications for the CLL community.

If you're not already registered with Inside Precision Medicine, it's free to do so.