UNLABELLED: Ionizing radiotherapy (RT) is a widely used treatment strategy for malignancies. In solid tumors, RT-induced double-strand breaks lead to the accumulation of insertion-deletions (indels; ID), and their repair by nonhomologous end joining has been linked to the ID8 mutational signature in surviving cells. However, the extent of RT-induced mutagenesis in hematologic malignancies and its impact on their mutational profiles and interplay with commonly used chemotherapies has not yet been explored. In this study, we interrogated 580 whole-genome sequence (WGS) samples from patients with large B-cell lymphoma, multiple myeloma, and myeloid neoplasms and identified ID8 only in relapsed disease. Yet ID8 was detected after exposure to both RT and mutagenic chemotherapy (i.e., platinum and melphalan). Using WGS of single-cell colonies derived from treated lymphoma cells, we revealed a dose-response relationship between RT and platinum and ID8. Finally, using ID8 as a genomic barcode, we demonstrate that a single RT-surviving cell may seed distant relapse. SIGNIFICANCE: RT and the ID8 indel signature are related, but their genomic impact on hematologic malignancies is unclear. Leveraging WGS, we linked ID8 to both RT and mutagenic chemotherapy and validated that platinum can induce ID8. We used ID8 as a genomic barcode to reveal that RT-resistant cells may seed systemic relapse.

Clinical Cooperation Unit Molecular Hematology Oncology Department of Internal Medicine 5 Heidelberg University Hospital Heidelberg University German Cancer Research Center Heidelberg Germany

Department of Hemato Oncology University Hospital Ostrava and Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Hematology Oncology and Clinical Immunology University Hospital Duesseldorf Duesseldorf Germany

Department of Oncology Hematology and Blood and Marrow Transplant University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Radiation Oncology Moffitt Cancer Center Tampa Florida

German Speaking Myeloma Multicenter Group Heidelberg Myeloma Center Department of Internal Medicine 5 Heidelberg University Hospital Medical Faculty Heidelberg University Heidelberg Germany

Heidelberg Myeloma Center Department of Internal Medicine 5 Heidelberg University Hospital Medical Faculty Heidelberg University Heidelberg Germany

Lymphoma Service Moffitt Cancer Center Tampa Florida

Lymphoma Service Sylvester Comprehensive Cancer Center Miami Florida

Myeloma Institute Sylvester Comprehensive Cancer Center University of Miami Miami Florida

Myeloma Research Program NYU Langone Perlmutter Cancer Center New York New York

Myeloma Service Memorial Sloan Kettering Cancer Center New York New York

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bioRxiv. 2024 Nov 18:2024.11.15.623836. doi: 10.1101/2024.11.15.623836. PubMed

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