Abstract
Abstract Introduction: In classical 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 long-term-responders (LTR). Methods: Therefore, ultra-deep next-generation panel-sequencing was performed on a total of 59 samples (20 LTR, 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. Results: Compared to LTRs, 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 LTRs and a significant selection process in favor of NOTCH-pathway mutations driving rHL or prHL was observed. Conclusion: This study delineates distinct mutational signatures between LTR and rHL/prHL, whilst illustrating longitudinal dynamics in mutational profiles using paired samples. Further, several exploitable therapeutic vulnerabilities for rHL and prHL were identified. Citation Format: Hanno Witte, Axel Künstner, Thomas Hahn, Veronica Bernard, Stephanie Stoelting, Kathrin Kusch, Kumar Nagarathinam, Nikolas von Bubnoff, Cyrus Khandanpour, Arthur Bauer, Michael Grunert, Annette Arndt, Konrad Steinestel, Hartmut Merz, Hauke Busch, Alfred Feller, Niklas Gebauer. The mutational landscape and its longitudinal dynamics in relapsed and refractory Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1747.
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