Complex Genomes in Cancer

Our aim is to develop new treatment strategies for patients with highly aggressive malignancies. To this end, we screen clinical tumor material for disease-causing mutations using deep sequencing technology and we manipulate genes of interest in cancer model systems to understand the true consequences of mutations.

Most high-grade cancers harbor mutations in the TP53 gene together with a massive amount of other mutations and chromosome aberrations. Disruption of the TP53 pathway is a well-known prerequisite for continued proliferation of cells with massively damaged DNA. However, the competitive advantage conferred by such a rearranged genome is largely unknown. This offers one of the most challenging paradoxes in cancer biology: what is required of a cell to not only survive massive genetic damage but also outcompete neighboring cells and present as a malignant tumor?

We study this phenomenon in osteosarcoma, a childhood malignancy that harbors one of the most rearranged genomes in cancer. The majority of osteosarcomas harbour mutations in the TP53 gene, either point mutations or structural variations that separate the promoter region from the coding parts of TP53. To enhance our understanding of the role of TP53 in cancer we focus on the TP53 promoter region – does it represent the gas or the brake pedal?