Comprehensive genomic profiling of Hodgkin Lymphoma employing liquid biopsies

• Applicant: Professor Dr. Andreas Engert
• Subject Area: Hematology, Oncology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 418041935

Hodgkin lymphoma is a B cell-derived, haematological malignancy. The peak incidence is in early adulthood. One of the remarkable features of Hodgkin lymphoma is the fact that the pathognomonic, malignant Hodgkin and Reed-Sternberg cells make up only a small percentage (1-10%) of the tumour tissue which poses a major technical challenge to comprehensive genomic profiling studies.Two challenges define the current medical need in Hodgkin lymphoma. First, the needed aggressive, multi-agent, front-line treatment leads to many early and late toxicities such as secondary cancers, cardiovascular disease, infertility, fatigue and osteonecrosis. Second, 10-30% of patients fail the first treatment attempt and approximately half of these often very young patients will ultimately die. Recently, we have established a liquid biopsy based targeted sequencing strategy for minimal residual disease diagnostics in Hodgkin lymphoma. We found that cell-free plasma DNA is highly enriched for tumour-derived DNA in Hodgkin lymphoma, considering the paucity of tumour cells in biopsies. We therefore performed a pilot study using a customized whole exome sequencing pipeline to evaluate the possibility of a comprehensive genomic profiling study of Hodgkin lymphoma using liquid biopsies. We were able to show that this is a feasible approach that can detect novel somatic alterations and comprehensively inform on the genomics of Hodgkin lymphoma.We now propose to extend our approach to 150 clinical trial patients for whom material and extensive clinical data including outcome is already available. We aim to use a novel, in-house developed liquid biopsy sequencing platform to create the first large, fully clinically annotated comprehensive genomic profile of newly diagnosed Hodgkin lymphoma and use it to (I) find novel genetic alterations in Hodgkin lymphoma as there is still an unsatisfied demand of a comprehensive genomic profiling study in Hodgkin lymphoma, (II) correlate both recurrent germline and somatic variants with comprehensively available clinical data, (III) develop novel risk classifications of Hodgkin lymphoma based on recurrent variants (e.g. identify high-risk or low-risk patients based on genetic information allowing to individualize and optimize treatment in the future), (IV) understand the clonal composition and heterogeneity of a patient's disease by capturing a snapshot of all the patient's tumour genome and (V) prove the feasibility of whole exome sequencing of liquid biopsies for clinical use and treatment individualization with relevance beyond Hodgkin lymphoma itself.We will comprehensively validate our findings with whole exome sequencing of available tumour biopsies and an independent dual analysis of a subset of samples with both the proposed whole exome sequencing approach and our already developed, also liquid biopsy based targeted sequencing strategy of selected recurrent genetic alterations of Hodgkin lymphoma at very high coverage ( > 1500x).

• DFG Programme: Research Grants