Complex Genomes in Cancer

The highly complex genome of an osteosarcoma.

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?

Selected publications

The links below will forward you to a new website.

CDK4 is co-amplified with either TP53 promoter fusions or MDM2 through distinct mechanisms in osteosarcoma. Saba KH, Difilippo V, Styring E, Nilsson J, Magnusson L, van den Bos H, Wardenaar R, Spierings D, Foijer F, Nathrath M, Haglund de Flon F, Baumhoer D, Nord KH. npj Genomic Medicine 2024;9:42. 

Disruption of the TP53 locus in osteosarcoma leads to TP53 promoter gene fusions and restoration of parts of the TP53 signalling pathway. Saba KH, Difilippo V, Kovac M, Cornmark L, Magnusson L, Nilsson J, van den Bos H, Spierings DCJ, Bidgoli M, Jonson T, Sumathi VP, Brosjö O, Staaf J, Foijer F, Styring E, Nathrath M, Baumhoer D, Nord KH. The Journal of Pathology 2024;262:147-160.

Osteosarcomas with few chromosomal alterations or adult onset are genetically heterogeneous. Difilippo V, Saba KH, Styring E, Magnusson L, Nilsson J, Nathrath M, Baumhoer D, Nord KH. Laboratory Investigation 2024;104:100283.

Complete list of publications

PubMed
ORCID: 0000-0002-2397-2254
My profile at the Lund University Research Portal

Networks in academia

• FOSTER (Fighting OsteoSarcoma Through European Research)
• Lund University Cancer Center
• Scandinavian Sarcoma Group

Funding

• The Swedish Childhood Cancer Fund
• The Swedish Cancer Society
• The Swedish state under the agreement between the Swedish government and the country councils, the ALF agreement

Popular science

Interview with the Swedish Childhood Cancer Fund