Oxford Myeloma Workshop 2025 | Multiomic insights into myeloma structural variants

In our research, we try to provide a better understanding of structural variants, which are genetic changes that are very common in multiple myeloma. They are involved in the development of the disease progression and also in treatment resistance. But what we often don’t think about, because there are large-scale changes, that not only are they changing the genes, for example, deleting genes within the region, but they are also reshaping how DNA is organized within the cell nucleus. And to access this information, we are not happy only to have genomic data, but we need to use multiomics, so newer technologies and deeper technologies or different molecular levels to really understand the consequence of any structural variant. 

So one of the technologies that we are introducing here is long-read sequencing where we are able to sequence much longer segments of DNA. So it’s something like when we solve a jigsaw puzzle, we can do the picture with very small pieces or we can have bigger pieces, so we do it with better confidence and much easier, and we know where each segment is going and how it’s changing in the patient. At the same time, long-read sequencing technology already offers to understand epigenomes, so like modifications of DNA, so we can immediately see what genes are impacted by structural variation, and on top of it, we are developing techniques where we can also look at modifications of the proteins that are important in the folding of DNA or how DNA interacts, and if we do that, we really see the complete picture of how structural variation is changing the genome, but also the epigenome and the folding of DNA in myeloma cells. 

So one point we make in our research is that in omics techniques, we rely on genome assembly, which is like a control human genome against which we compare our samples, and the problem is that if we do so, we kind of miss part of our genome because these references are not perfect. So we are using one of the latest assemblies that was developed by the Telomere to Telomere Consortium, so we can access regions that we could not really analyze before. So we are looking at, like, centromeric regions, telomeric regions, and genome gaps that are very challenging to understand. 

And one of the changes that is related, and we are showing some data about, is 1q gain, which is very common in multiple myeloma and is associated with a not very good prognosis. And we call it 1q gain because there is additional material on chromosome 1, but physically, by the principle of chromosomal biology, this material has to be attached somewhere, but because the breakpoint is in the genome gap of previous assemblies, we were not able to see it. So we are trying to resolve this part of the puzzle. So we developed methods where we can fully understand the shape of this abnormality, and basically see one q gain as chromosomal translocation, and we see that where 1q gain of the additional material gets stuck to, that there are some epigenomic reprogramming. So I’m looking at if that is also associated with the consequence of the worst prognosis for patients.

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