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

Hanno Witte; Axel Künstner; Thomas Hahn; Veronica Bernard; Stephanie Stölting; Kathrin Kusch; Kumar Nagarathinam; Cyrus Khandanpour; Nikolas von Bubnoff; Arthur Bauer; Michael Grunert; Svenja Hartung; Annette Arndt; Konrad Steinestel; Hartmut Merz; Hauke Busch; Alfred C. Feller; Niklas Gebauer

doi:10.1007/s00277-025-06274-5

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

Hanno Witte^*, Axel Künstner, Thomas Hahn, Veronica Bernard, Stephanie Stölting, Kathrin Kusch, Kumar Nagarathinam, Cyrus Khandanpour, Nikolas von Bubnoff, Arthur Bauer, Michael Grunert, Svenja Hartung, Annette Arndt, Konrad Steinestel, Hartmut Merz, Hauke Busch, Alfred C. Feller, Niklas Gebauer

^*Corresponding author for this work

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.

Original language	English
Article number	e1009935
Journal	Annals of Hematology
Volume	104
Issue number	3
Pages (from-to)	1721-1733
Number of pages	13
ISSN	0939-5555
DOIs	https://doi.org/10.1007/s00277-025-06274-5
Publication status	Published - 03.2025

Research Areas and Centers

Research Area: Luebeck Integrated Oncology Network (LION)
Centers: University Cancer Center Schleswig-Holstein (UCCSH)
Research Area: Medical Genetics

DFG Research Classification Scheme

2.22-14 Hematology, Oncology
2.11-05 General Genetics and Functional Genome Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s00277-025-06274-5

Cite this

Witte, H., Künstner, A., Hahn, T., Bernard, V., Stölting, S., Kusch, K., Nagarathinam, K., Khandanpour, C., von Bubnoff, N., Bauer, A., Grunert, M., Hartung, S., Arndt, A., Steinestel, K., Merz, H., Busch, H., Feller, A. C., & Gebauer, N. (2025). The mutational landscape and its longitudinal dynamics in relapsed and refractory classic Hodgkin lymphoma. Annals of Hematology, 104(3), 1721-1733. Article e1009935. https://doi.org/10.1007/s00277-025-06274-5

@article{7c42587e74d04539bb68ee843c439f3b,

title = "The mutational landscape and its longitudinal dynamics in relapsed and refractory classic Hodgkin lymphoma",

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.",

author = "Hanno Witte and Axel K{\"u}nstner and Thomas Hahn and Veronica Bernard and Stephanie St{\"o}lting and Kathrin Kusch and Kumar Nagarathinam and Cyrus Khandanpour and {von Bubnoff}, Nikolas and Arthur Bauer and Michael Grunert and Svenja Hartung and Annette Arndt and Konrad Steinestel and Hartmut Merz and Hauke Busch and Feller, {Alfred C.} and Niklas Gebauer",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = mar,

doi = "10.1007/s00277-025-06274-5",

language = "English",

volume = "104",

pages = "1721--1733",

journal = "Annals of Hematology",

issn = "0939-5555",

number = "3",

}

Witte, H, Künstner, A, Hahn, T, Bernard, V, Stölting, S, Kusch, K, Nagarathinam, K , Khandanpour, C , von Bubnoff, N, Bauer, A, Grunert, M, Hartung, S, Arndt, A, Steinestel, K, Merz, H, Busch, H, Feller, AC & Gebauer, N 2025, 'The mutational landscape and its longitudinal dynamics in relapsed and refractory classic Hodgkin lymphoma', Annals of Hematology, vol. 104, no. 3, e1009935, pp. 1721-1733. https://doi.org/10.1007/s00277-025-06274-5

TY - JOUR

T1 - The mutational landscape and its longitudinal dynamics in relapsed and refractory classic Hodgkin lymphoma

AU - Witte, Hanno

AU - Künstner, Axel

AU - Hahn, Thomas

AU - Bernard, Veronica

AU - Stölting, Stephanie

AU - Kusch, Kathrin

AU - Nagarathinam, Kumar

AU - Khandanpour, Cyrus

AU - von Bubnoff, Nikolas

AU - Bauer, Arthur

AU - Grunert, Michael

AU - Hartung, Svenja

AU - Arndt, Annette

AU - Steinestel, Konrad

AU - Merz, Hartmut

AU - Busch, Hauke

AU - Feller, Alfred C.

AU - Gebauer, Niklas

PY - 2025/3

Y1 - 2025/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85218692659&partnerID=8YFLogxK

U2 - 10.1007/s00277-025-06274-5

DO - 10.1007/s00277-025-06274-5

M3 - Journal articles

C2 - 39992429

AN - SCOPUS:85218692659

SN - 0939-5555

VL - 104

SP - 1721

EP - 1733

JO - Annals of Hematology

JF - Annals of Hematology

IS - 3

M1 - e1009935

ER -

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

Abstract

Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this