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iwNHL 2025 | Capturing and targeting the molecular heterogeneity in diffuse large B-cell lymphoma
In this interview, Margaret Shipp, MD, Dana-Farber Cancer Institute, Boston, MA, discusses molecular heterogeneity in diffuse large B-cell lymphoma (DLBCL), highlighting the two aspects of this heterogeneity that have been studied. Dr Shipp suggests that identifying distinct genetic signatures in patients with DLBCL may allow for individualized targeted therapy to improve outcomes. This interview took place at the 22nd International Workshop on Non-Hodgkin Lymphoma (iwNHL 2025), held in Cambridge, MA.
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Transcript
So there are two different aspects of molecular heterogeneity that people have looked at over the years. Initially, a number of years ago, there was a lot of investigation into the RNA-based transcriptional subtypes that seemed to be aligned with cells of origin. And the reason this was interesting is it was associated with differences in outcome. So that’s something people have looked at historically, and more recently, we’ve looked at DNA-based genetic heterogeneity and identified discrete clusters of DLBCL that seem to be driven by combinations of genetic alterations and perturbation of pathways...
So there are two different aspects of molecular heterogeneity that people have looked at over the years. Initially, a number of years ago, there was a lot of investigation into the RNA-based transcriptional subtypes that seemed to be aligned with cells of origin. And the reason this was interesting is it was associated with differences in outcome. So that’s something people have looked at historically, and more recently, we’ve looked at DNA-based genetic heterogeneity and identified discrete clusters of DLBCL that seem to be driven by combinations of genetic alterations and perturbation of pathways. This is interesting for a couple of reasons. One is that the outcome associated with these different molecular clusters is different, and it provides some additional insights into heterogeneity that is not captured just with the earlier RNA-based transcriptional signatures. And the other reason it’s interesting is it provides some insights in terms of how you might think about targeted therapies. So certain genetic signatures that are associated with perturbing certain pathways really suggest targets and targeted agents that might be selectively beneficial in subtypes of the disease, but not others.
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