A new perspective on the genetics of classical Hodgkin lymphoma through liquid biopsy
Institutional Communication Service
An international study conducted by the Experimental Hematology research group at the Institute of Oncology Research (IOR), in collaboration with the Oncology Institute of Southern Switzerland (IOSI), led by Prof. Davide Rossi — Group Leader at IOR and Deputy Head of Hematology at IOSI — and recently published in Blood, has redefined the genetic understanding of classical Hodgkin lymphoma (cHL) through the use of circulating tumor DNA (ctDNA).
Background
Hodgkin lymphoma is among the most curable cancers, yet standard therapies may cause significant long-term side effects. Current research is therefore moving toward more personalized approaches, aiming to reduce treatment toxicity without compromising effectiveness. A deeper understanding of the genetic mechanisms driving the disease is a crucial step in this direction.
The discovery
The research involved more than 300 patients enrolled in two multicenter studies, aiming to map the genetic landscape of cHL and to connect it with disease biology and clinical outcomes.
Two distinct genetic subtypes
Through ultra-deep sequencing of ctDNA, the investigators identified two major genetic subtypes of cHL, driven by different mechanisms of genomic instability:
- The “hypermutated” subtype (64% of cases), with a high mutational burden and signatures linked to activation-induced cytidine deaminase (AID) and microsatellite instability.
- The “chromosomal instability” subtype (36% of cases), marked by numerous somatic copy number alterations (SCNA).
This classification suggests that, unlike other B-cell lymphomas, the subtypes of cHL are not defined by specific functional mutations, but rather by broader mechanisms of genetic instability.
New vulnerabilities and prognostic biomarkers
A particularly innovative finding of the study was the discovery of recurrent noncoding regulatory mutations in the BCL6 gene, found in about 30% of cases. These mutations drive aberrant BCL6 expression in Hodgkin lymphoma cells, pointing to a potential therapeutic vulnerability. In preclinical models, pharmacological degradation of BCL6 impaired tumor cell proliferation.
Another key observation was the high frequency of whole-genome duplication (WGD) in cHL (24% of patients). WGD was associated with inferior outcomes in patients treated with standard ABVD chemotherapy, and it emerged as an independent prognostic biomarker.
Clinical implications: ctDNA outperforms PET?
The study also assessed ctDNA as a tool for treatment monitoring. Persistent ctDNA after therapy proved to be a highly accurate predictor of relapse, with better prognostic value than PET/CT scans. This highlights the potential of liquid biopsy to distinguish true residual disease from false-positive imaging findings, reducing unnecessary treatments.
Towards personalized therapies
Overall, this work provides the most comprehensive genetic characterization of classical Hodgkin lymphoma to date. By identifying distinct genetic subtypes, uncovering novel vulnerabilities such as BCL6, and establishing new prognostic markers like WGD and ctDNA response, this research lays the groundwork for more personalized treatment strategies that could improve patient outcomes.
The study
“A comprehensive genetic study of classic Hodgkin lymphoma using circulating tumor DNA”: https://www.sciencedirect.com/science/article/pii/S0006497125011851?dgcid=author
