# The mutational landscape and its longitudinal dynamics in relapsed and refractory classic Hodgkin lymphoma

## TL;DR

This study explores the genetic differences in Hodgkin lymphoma patients who do not respond to treatment or relapse, identifying specific mutations that could lead to new therapies.

## Contribution

The study identifies novel mutational signatures and longitudinal dynamics in relapsed and refractory classic Hodgkin lymphoma using ultra-deep sequencing.

## Key findings

- Mutations in genes like PMS2, PDGFRB, KAT6A, EPHB1, and HGF are more frequent in refractory/relapsed cHL.
- NOTCH pathway mutations are selected in relapsed/refractory cHL, while hippo-pathway mutations are negatively selected.
- Distinct mutational profiles between responders and non-responders were identified, suggesting therapeutic vulnerabilities.

## Abstract

In classic Hodgkin-lymphoma (cHL), only a few cases recur, and only a limited fraction of patients is primary-refractory to standard-polychemotherapy. Underlying genomic features of unfavorable clinical courses remain sparsely characterized. Here, we investigated the genomic characteristics of primary-refractory/relapsed cHL in contrast with responders. Therefore, ultra-deep next-generation panel-sequencing was performed on a total of 59 FFPE-samples (20 responders, 26 relapsed (rHL: 11 initial-diagnosis, 15 relapse) and 13 primary-refractory (prHL: 8 initial-diagnosis, 5 progression) from 44 cHL-patients applying a hybrid-capture approach. We compared samples associated with distinct disease courses concerning their oncogenic drivers, mutational signatures, and perturbed pathways. Compared to responders, mutations in genes such as PMS2, PDGFRB, KAT6A, EPHB1, and HGF were detected more frequently in prHL/rHL. Additionally, we observed that in rHL or prHL, BARD1-mutations occur, whereas ETV1, NF1, and MET-mutations were eliminated through clonal selection. A significant enrichment of non-synonymous variants was detected in prHL compared to responders and a significant selection process in favor of NOTCH-pathway mutations driving rHL or prHL was observed. However, our analysis revealed a negative selection process for non-synonymous variants affecting the hippo-pathway. This study delineates distinct mutational signatures between responders and rHL/prHL, whilst illustrating longitudinal dynamics in mutational profiles using paired samples. Further, several exploitable therapeutic vulnerabilities for rHL and prHL were identified.

The online version contains supplementary material available at 10.1007/s00277-025-06274-5.