Whole-genome sequencing reveals key structural information about Hodgkin lymphoma
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A multi-institutional research project has demonstrated the superior value of whole-genome sequencing vs. exome sequencing in providing information about classic Hodgkin lymphoma.
Researchers from Sylvester Comprehensive Cancer Center in University of Miami Miller School of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College showed that whole-genome sequencing (WGS) can better detect DNA structural variations and offers more specific data to track mutations linked to disease progression. The study appeared in Blood Cancer Discovery.
“Whole-exome sequencing has been used for the past 10 to 15 years to characterize carcinogenic mutations,” Francesco Maura, MD, assistant professor of medicine and co-leader of the myeloma genomic lab at the Sylvester Comprehensive Cancer Center, told Healio. “Exome sequencing has expanded our understanding, of course. We identify mutations that can be used as therapeutic targets, but the difference is that exome sequencing only covers 3% of the genome. We know that cancer is shaped by multiple alterations that occur in the noncoding part of the genome, such as copy number changes and structural variants.”
Maura spoke with Healio about the rationale for his study, its implications and what he aims to achieve next in this area.
Healio: How does WGS provide better information than exome sequencing regarding genetic changes that drive cancer development and growth?
Maura: WGS allows you to capture the entire genome and then gives you a resolution of essentially all possible somatic events that cancer can acquire. In particular, it gives you information about structural variants, tumor mutational burden and which mutation processes are active in our tumor cells. Also, because you have all this additional information, it becomes easier to reconstruct the order of events — what is clonal, what is nonclonal, what is early and what is late.
Healio: Can WGS provide information about how a particular tumor evolved?
Maura: It depends. WGS doesn’t have the depth or resolution that the whole exome has. You cannot go as deep, but because you have more information, you can play with different mathematical modelings to estimate when different events are acquired in relation to one another. That’s very important and can provide relevant information that can be used to identify the right therapeutic targets.
Healio: What inspired you to study WGS for evaluating classic Hodgkin lymphoma?
Maura: Hodgkin lymphoma is a disease that has never been characterized by WGS, so all the observations were made using exomes or targeted panels. There are other ways of gaining important information, such as liquid biopsy, that are extremely valuable but restrictive — not allowing the capture of structural variants or mutational signatures in each tumor. You can sequence a genome and find no structural variants, as can occur in certain leukemias. In the case of Hodgkin lymphoma, though, we found a very highly advanced complexity, which revealed that WGS can be extremely informative in defining these variants.
Healio: What types of valuable information did WGS provide?
Maura: We were amazed by the number of events, the complexity of these events and how they were accumulated over time. It was an extremely exciting and interesting journey. We found a very high mutational burden, which basically means the Hodgkin lymphoma cells accumulate more mutations than most of the hematologic cancers. We think our estimates might be underestimating the real burden because sequencing Hodgkin is not easy. You have a few cells you have to amplify, and you have to apply very strict quality control. We think the mutational burden is actually closer to that of melanoma and lung cancer, which is in line with other exome sequencing-based studies. We know Hodgkin lymphoma is very sensitive to PD-1 and PD-L1 inhibitors such as pembrolizumab (Keytruda, Merck) and nivolumab (Opdivo, Bristol Myers Squibb). This high mutational burden could be another possible explanation as to why they are so effective.
Healio: What are the implications of this study? Should patients with Hodgkin lymphoma be advised to undergo WGS?
Maura: I don’t think we are ready for that. It also might be extremely difficult to do in the clinic — not because of the cost, because costs are going down for WGS. The difficulty is mainly related to the limited number of cells. WGS is an extremely complicated approach, and in Hodgkin it’s not easy. Logistical challenges arise in getting to the samples and using them. It might be difficult for us to do in the clinic.
We know liquid biopsy works — you can capture a lot of information about Hodgkin from the circulating DNA. Nevertheless, liquid biopsy is often restricted to a set of genes. It cannot capture structural variants in an unbiased way, meaning you need to know what you’re looking for to capture that with high sensitivity. It’s hard to discover new things in a comprehensive way. The comprehensive resolution of WGS is definitely not available in liquid biopsy.
The future I foresee is an integration, where WGS will define which key genomic events are the most important — and the ones that are also prognostic — and use them to generate surrogate markers we can test for. Once we have that, there won’t be a need for complex logistical efforts.
Healio: Is there anything else that you think would be important to mention?
Maura: Going forward, we need to collaborate and synergize our efforts. I hope to get more samples and more data paired with clinical outcomes, which were missing in our data. We want to have a better understanding of the key drivers.
Another aspect that our paper touched on briefly is the mutagenic effect of certain chemotherapy. We know that in Hodgkin, particularly in certain kinds of Hodgkin and certain age populations, the outcome is extremely favorable. So, it’s basically a model for different cancers. Once you achieve such a great result, you don’t work to increase efficacy that is hard to improve. Instead, you work around reducing the long-term toxicity. So, we’re working in that direction.
In our paper, we indirectly found a mutational signature called SBS25 in patients exposed to ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine)-like cycles, in which all the drugs but dacarbazine and procarbazine are nonmutagenic. We know from in vitro and other experiments that they do not introduce mutations. So, indirectly, you can say the only chemotherapies left are dacarbazine and procarbazine, which we’ve known to be mutagenic since the 1990s. We know chemotherapy has been associated with increased risk for developing secondary tumors. This is part of a larger effort, not just in terms of etiology, prognosis or genomic events affecting the outcome, but in understanding what we can do to reduce or mitigate the long-term adverse effects of chemotherapy in this population.
For more information:
Francesco Maura, MD, can be reached at fxm557@med.miami.edu; Twitter: @FrancescoMaura4.
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Maura F, et al. Blood Cancer Discov. 2023;doi:10.1158.2643-3230.BCD-22-0128.
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