Abstract 152P
Background
A variety of recurrent chromosomal translocations have been characterized from rare cancer patient tumors, which result in fusion oncogenes that play essential roles in disease pathogenesis. For instance, the t(11:22)(q24:q212) translocation in Ewing’s sarcoma fuses the transcriptional regulatory domains of EWSR1 to the DNA binding domain of the FLI1 gene, causing aberrant FLI1 activation and expression. However, the roles of many fusion oncogenes in rare cancers are unknown, including why specific fusions recur in certain diseases arising from different tissues. We postulate that the tissue-specificity of rare cancer fusion oncogene incidence is driven by a mix of positive selection in permissive tissues and stress-induced negative selection in non-permissive tissues.
Methods
We performed a combination of computational and fusion gene overexpression studies.
Results
Meta-analysis of fusion gene partnerships found in rare cancers suggests that diseases arising from the same tissue tend to select fusions from overlapping gene sets. Overexpressing EWSR1-CREB1 in a 'non-permissive' tissue (mammary epithelial cells) led to apoptosis, whereas 'native' fusions found in breast cancers could be stably expressed without causing cellular stress. To further investigate this phenomenon, we titrated the expression level of 4 fusion oncogenes using a doxycycline inducible promoter in healthy cell lines derived from different tissues and conducted bulk mRNA sequencing across a range of fusion doses. We then compared our in vitro data to tumors containing each fusion to analyze differences in transcriptomic landscapes. We found that EWSR1-CREB1 induced an inflammatory response (such as upregulation of IL6) and reduced cell cycle gene expression in a dose-dependent manner in mammary epithelial cells. Tumors containing EWSR1-CREB1 revealed partially similar gene expression profiles, including upregulation of inflammatory signaling.
Conclusions
However, how these profiles may lead to tumorigenesis in soft tissues but not mammary tissues is unknown. Further analyses of fusion oncogene effects across tissues will reveal key insights to the role fusions play in rare cancer disease pathogenesis, and their restriction to certain cell types during tumorigenesis.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
UMass Chan Medical School.
Disclosure
All authors have declared no conflicts of interest.