Poster Presentation 25th Lorne Cancer Conference 2013

Phylogenetic analysis of clonal evolution of acquired drug resistance in liposarcoma  (#189)

David Goode 1 , Arcadi Cipponi 1 , David Thomas 1
  1. Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia

Tumours comprise populations of related but genetically distinct cell lineages with unique cellular traits subject to selection. This variation allows a tumour to survive in the face of intense environmental pressures, such as exposure to chemotherapeutic drugs. Artificial selection in the laboratory using the 778 liposarcoma cell line has produced lines resistant to the MDM2-inhibitor Nutlin-3a, providing a model system to study acquired drug resistance and tumour evolution.

We isolated individual clones from 778 and a Nutlin-resistant descended from it via artificial selection, R252. The phenotype of each clone has been extensively characterized, and the exomes of 12 clones from each population were sequenced. By constructing a phylogeny between clones based on the exome sequence data, we can map changes in population structure that occurred in response to exposure to Nutlin, including the severity of the population bottleneck induced by the drug.

Phylogenetic analysis, coupled with gene expression and DNA methylation data, also reveals putative selected loci. Preliminary results indicate genes related to genomic stability and copy-number driven alterations in DNA methylation are associated with acquisition of Nutlin resistance.