Hereditary predisposition in pediatric brain cancer

• Applicant: Lena Kutscher, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 497317859

Pediatric cancer is the leading cause of disease-related death in children, and solid tumors of the central nervous system account for approximately 20% of all pediatric cancer. In SHH-medulloblastoma, a childhood tumor arising from the developing cerebellum, hereditary predisposition genes accounts for near 40% of all cases. This proposal investigates the molecular function of ELP1, a novel hereditary predisposition gene in SHH-medulloblastoma. ELP1 encodes the scaffolding member of the Elongator complex, which is implicated in tRNA modification and efficient translation, but its role in tumorigenesis is unknown. We previously determined that Elp1 is required for a healthy cerebellum, as homozygous loss in the cell-of-origin, the granule cell progenitor (GCP), increases cell stress and death, through an increase in the cell cycle inhibitor P21. Interestingly, we found that heterozygous loss of Elp1 had the opposite effect: namely a dampened DNA damage response. Therefore, in this proposal, we will investigate the molecular underpinnings of the medulloblastoma predisposition gene ELP1 in the DNA damage response pathway, building upon our work from the first DFG funding period. We will 1) investigate the molecular mechanism behind dampened DNA damage response in irradiated ELP1HET cells; and 2) uncover the long-term consequences of DNA instability in ELP1HET cells. We will use a combination of human induced pluripotent stem cell derived GCP models, molecular biology and biochemistry to uncover the role of ELP1 in the DNA damage response. Given its prevalence in SHH-medulloblastoma hereditary predisposition, our results may have the possibility to help many patients.

• DFG Programme: Research Grants