Integrating Structural and Functional Cancer Genomics: Dissecting Molecular Mechanisms in Aggressive B-Cell Lymphomas

• Applicant: Professor Dr. Roland Schmitz
• Subject Area: Hematology, Oncology ; General Genetics and Functional Genome Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 490993992

While cancer genome sequencing studies have mapped the mutational landscape of many cancer types, it remains a challenge to identify and understand the functional oncogenic events that drive the genesis and survival of the cells of malignant neoplasms. However, recent biotechnological advances are enabling functional genomics experiments on a scale that can match the pace of genome sequencing. The goal of the proposed project is to utilize more than 700 genome, exome and targeted sequencing datasets, genome-wide CRISPR/Cas9 screens, and targeted mechanistic analysis of candidate genes to decipher the pathophysiological mechanisms in MYC-associated aggressive B-cell lymphomas such as Burkitt lymphoma and high grade diffuse large B cell lymphoma. Integrative bioinformatic pipelines will characterize genetic distinctions between lymphoma sub-groups and enable the identification of candidate lymphoma oncogenes and tumor suppressors. Cell line models of the genetic subtypes of the studied lymphomas will be used in loss-of-function screens to mechanistically evaluate pathways that are targeted by genetic aberrations. Comparison of the functional gene sets between genetic subgroups of lymphomas will identify genes and pathways that are essential for lymphoma cells harboring particular genotypes. Gene variants found to induce and maintain a malignant phenotype will be validated and mechanistically analyzed in detail. The proposed project will close the gap between the description of genetic alterations in MYC-associated aggressive B-cell non-Hodgkin lymphomas and its functional interpretation. Systematic genetic approaches and targeted mechanistic investigations will be combined to identify pathologi-cally significant driver mutations. Of particular interest will be oncogenic events that are essential only for specific genetic subgroups of B-cell lymphomas. Elucidating these context-specific cancer vulnerabilities will provide a more complete understanding of the fundamental processes that drive lymphomagenesis and will guide future precision medicine approaches.

• DFG Programme: Research Grants