Genetic Predisposition

The NCT/UCC Research Group “Genetic Predisposition” focuses on the identification of disease causing germline variants/alterations in children with cancer with a special focus on acute leukemia of childhood, as well as the elucidation of the oncogenic capacity of these genetic variants in regard to environmental exposures.

Current studies report an involvement of classical and newly identified germline predisposition genes in up to 10% of pediatric cancers. While the routine sequencing of germline/tumor tissue from the patient provides the potential to uncover novel disease causing variants, this approach is not sufficient to fully understand the genetic origin, etiology and the penetrance of the respective disease. Therefore, our group integrates a more powerful and comprehensive strategy, which is based on next generation sequencing of child-parent trios (trio-sequencing). Thereby identified predispositions are reported back to participating families, giving them the opportunity of genetic counseling, individualized therapy adaptation and surveillance. Variants of unknown significance (VUS) are further thoroughly characterized by a combination of bioinformatics and molecular biological methods utilizing in-vitro as well as in-vivo models. In this regard our group takes particular interest in inherited polygenic VUS in childhood leukemia  and the interplay of genetic predisposition to leukemia and exposure to infection. We analyze the role of genetic predisposition and leukemia using a unique approach, since we leave the conventional way of studying mouse models in pathogen free animal facilities (SPF), and precisely reproduce the human leukemia phenotype during conventional facility (CF) housing (exposure to common pathogens).

• Trio-sequencing of child-parent trios in children newly diagnosed with cancer
• Analysis of the sequencing data for known classical cancer predispositions and VUS
• Transfection, Transduction, Knockdown and Overexpression in cell systems
• CRISPR-Cas9 based technologies
• Protein biochemical methods (Western Blot, Immunoprecipitation, Reporter gene assays)
• Sequencing methods (NGS, Sanger-sequencing, Deep-Sequencing) (in cooperation)
• Transgenic mouse models