Unraveling clonal dynamics and evolutionary trajectories in neuroblastoma

• Applicant: Privatdozentin Dr. Carolina Rosswog
• Subject Area: Pediatric and Adolescent Medicine ; Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558002299

Neuroblastoma develops from the sympathetic nervous system and presents with maximum divergent clinical courses, ranging from spontaneous regression to fatal progression despite multimodal treatment. At the time of diagnosis, neuroblastoma typically harbors a low mutational load, which frequently increases at the time of relapse. The principles of clonal evolution in neuroblastoma and their contribution to disease recurrence and therapy resistance, however, have remained unclear. We therefore aim at unraveling the clonal dynamics and evolutionary trajectories in neuroblastoma by comprehensively examining genomic alterations in longitudinal samples of a unique cohort of primary neuroblastomas. We expect that our approach will significantly contribute to uncovering the mechanisms driving disease evolution, therapeutic resistance, and relapse. To achieve our goal, we will analyze whole-genome and/or whole-exome sequencing (WGS; WES) data of 151 longitudinal tumor samples obtained from 58 neuroblastoma patients. We will investigate how both, oncogenic mutations and structural alterations evolve over treatment and at relapse, and determine patterns of clonal composition and diversification within tumors over time. As complementary analyses, we will include RNA sequencing data of the same tumors to track expression patterns over time, and linked-read WGS data to unravel complex structural alterations. In addition, we will utilize fluorescence in situ hybridization, immunofluorescence, and immunohistochemical staining, as well as imaging mass cytometry to not only validate genomic alterations or their molecular consequences, but also to thoroughly characterize the spatial composition of tumors on the cellular level over the course of disease. By integrating data from sequencing approaches and complementary experiments, we aim to precisely determine how somatic alterations contribute to tumor heterogeneity and how these changes are distributed across distinct cell types within the tumor. Most importantly, we will also associate our findings from molecular analyses with in-depth clinical data of the patients, including detailed records on patient characteristics, treatment regimens, and long-term outcome. This approach will be crucial to evaluate the clinical relevance of somatic alterations and evolutionary patterns. Together, our project aims to gain deep insights into the genomic evolution of neuroblastoma, especially in high-risk cases, to better understand the mechanisms of tumor progression, therapy resistance, and relapse. These insights will be crucial for identifying potential targets and developing future therapeutic strategies for this deadly malignancy.

• DFG Programme: Research Grants