COMy 2023 | How is the genomic landscape of multiple myeloma changing?
Gareth Morgan, MD, PhD, FRCP, FRCPath, NYU Langone Health, New York City, NY, shares some insights into how the genomic landscape of multiple myeloma has changed over the years, and advances that have been made. Prof. Morgan explains that research is beginning to focus more on non-coding regions of the genome, and further shares some insights into how various mutational signatures play a role in disease, including the APOBEC mutational signature. This interview took place at the 9th World Congress on Controversies in Multiple Myeloma (COMy) 2023, held in Paris, France.
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Transcript (edited for clarity)
So, the genomic landscape of myeloma has changed dramatically I think, in the last five to six years. So it’s kind of crept up on people a little, I think, the amount of change that’s happened. Originally we focused on the coding genome, which is only 2% of the total and we defined the mutations that define myeloma. And so they fall into a pathway called the Ras-MAP kinase pathway. So 50% of patients with myeloma have a mutation in that pathway...
So, the genomic landscape of myeloma has changed dramatically I think, in the last five to six years. So it’s kind of crept up on people a little, I think, the amount of change that’s happened. Originally we focused on the coding genome, which is only 2% of the total and we defined the mutations that define myeloma. And so they fall into a pathway called the Ras-MAP kinase pathway. So 50% of patients with myeloma have a mutation in that pathway. So yeah, great, we could target that going forward. But now we’ve started focusing on the non-coding regions of the genome and it’s told us all sorts of new things so we can define signatures of mutations. And it turns out that in myeloma there’s a specific signature called APOBEC, which illustrates how the disease is driven, which is by an overreaction to inflammatory change in the germinal center, which puts these mutations into the cancer cells. The other signature we’ve seen is one that defines exposure to melphalan as part of high-dose melphalan, and so you can see evidence that the treatment drives the progression of the disease because the disease has a specific pattern of mutations caused by that treatment. So that’s another major step forward. The third thing that we really notice is a focus on structural events which tend to occur in the non-coding region and is where one region of the genome moves to another part. So it’s a different type of mutation and these mutations lead us from looking at this kind of linear genome where everything is in a straight line which is clearly not biologically relevant to this 3D genome where the DNA is folded, packed into the nucleus and you take account of these 3D structures. So when you do that, it leads you to look at super enhancers, gene control regions and these structural events are really impacting gene control, leading to overexpression of oncogene drivers. And if we can find those oncogene drivers, I think we can target treatment against them. So it’s a very exciting time in the genomics of myeloma and people are really starting to make progress.
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