(P 268) IMPACT OF CELLULAR FUSION IN THE ONCOGENESIS OF LEIOMYOSARCOMAS

Objective: Leiomyosarcoma (LMS) is one of the most common and aggressive type of soft tissue sarcomas. Around 50% of the patients develop metastasis translating in an overall survival rate of 12 months after the dissemination of the disease. LMS are very heterogeneous and they show highly rearranged genome with no recurrent alterations. The treatment options for LMS are still restricted, the development of deeper knowledge in LMS genomics could uncover key biological features for the design of new therapeutically strategies. While whole genome doubling is very frequent in LMS oncogenesis, the mechanism leading to tetraploidization is unknown. We hypothesized that cell fusion is one of the mechanisms contributing to LMS oncogenesis, heterogeneity and chaotic genome.

Methods: To asses this hypothesis, we produced a spontaneous cell fusion model between fibroblast and smooth muscle cells, in which we observed, additional to a highly rearranged genome, a very specific break point deletion in chromosome 10, in the gene PRKG1. PRKG1 is involved in smooth muscle contractile function and cellular proliferation. We also use primary LMS cell lines with PRKG1 deletion to unveil the different cell lines’ phenotypes. To further study the frequency and role of PRKG1, we analyze whole genome sequencing (WGS), comparative genome hybridization (CGH) and RNA sequencing from LMS tumor samples and cell lines.

Results: After studying a cohort of 123 LMS patients in whole genome sequencing (WGS), we observed that the deletion of PRKG1 was frequent (14%). This makes PRKG1 be among the five most commonly altered genes in LMS. Phenotypic analysis were performed comparing cell lines where PRKG1 was deleted with their overexpress counterparts. Results show that when PRKG1 is deleted cell lines have a higher migration rate. Low PRKG1 expression is also associated with poor overall and metastatic survival of LMS patients.

Conclusion: In conclusion, with this cell fusion model we revealed that cell fusion could be one of the mechanisms involved in the development of LMS through genome reshuffling. PRKG1 deletion/down regulation, triggered by genome merging, is therefore associated with tumor evolution.