PO-508 Detection and role of novel fusion oncogenes in paediatric cancers

Abstract

IntroductionPaediatric cancers (PC) represent the 1 st cause of death by disease in children as 20% of patients still die from a recurrence of the malignancy. PC differ from adult cancers regarding their aetiology, cellular origin or mutational rate. Improving the knowledge on the biology of the relapsed tumours and identifying new targets are needed to provide new treatments. Fusion genes are responsible for ~20% of cancers and are the consequence of the juxtaposition of two previously separate genes which can activate proto-oncogenes or inactivate tumour suppressor genes. They are of great interest in clinics as they can be used as therapeutic targets or biomarkers. Our aim is to explore new fusion genes in relapsing/resistant paediatric patients through bioinformatics analysis of the NGS data from the molecular profiling program MOSCATO-01, and to study their function and oncogenic potential.Material and methodsWe developed an approach to optimise the detection of fusion transcripts in RNA-seq data. A biological validation of selected candidates was performed by RT-qPCR in patients’ tumour samples and available cell lines. A fusion never previously described found in a Ewing’s sarcoma (EWS) patient retained our attention, therefore we established 2 cellular models in order to assess the effect of this transcript on proliferation, migration, sensitivity to anticancer agents, gene expression in vitro and tumorigenicity in mice.Results and discussionsOur in-house pipeline ChimComp allowed the detection of 118 new potentially oncogenic fusions. Following the validation by RT-qPCR, we showed that ChimComp could be reliable at ~90%. A new fusion, LMO3-BORCS5, was found in a patient with EWS and in 12 cell lines from different origins suggesting that it is not an isolated event. Then, we explored the function and oncogenic potential of LMO3-BORCS5. Until now, we show that the stable transfection of this fusion into A673 Ewing’s sarcoma and NIH3T3 murine fibroblasts cell lines, leads to an increase of cell proliferation and an increase or an induction of tumorigenicity after injection in mice, as well as a decrease of sensitivity to anticancer drugs vincristine and camptothecin in A673 cells.ConclusionThese results suggest that LMO3-BORCS5 could play a key role in tumorigenesis and in response to treatment and could be used as a therapeutic target for patients where LMO3-BORCS5 is detected. More broadly, this study emphasises the key role of fusion genes in disease progression and their clinical interest in personalised medicine.