Tetraploidization-driven PRKG1 deletion reveals novel mechanisms underlying Leiomyosarcoma aggressiveness

Leiomyosarcoma (LMS) is a malignant mesenchymal tumor with smooth muscle cell (SMC) differentiation. LMS shows high metastatic rate and highly rearranged genome, associated with whole genome doubling, which is identified in more than half of cases. We tested the hypothesis that cell fusion could be one of the mechanisms involved in the development of genome doubling and the production of multiple genomic alterations. We developed a cellular fusion model between SMCs and fibroblasts to compare the genomic alterations found in the hybrid cells vs the genomic profiles of LMS patients. This cell fusion model revealed a recurrent deletion within PRKG1 in chromosome 10, gene involved in smooth muscle contractile function and proliferation. The whole genome sequencing (WGS) analysis of a cohort of 121 LMS patients revealed that 76.9% (93/121) of patients had at least one PRKG1 altered copy, from which 18.2% (17/93) showed either a breakpoint (BP) in PRKG1 or an intra-chromosomal deletion surrounding PRKG1 . RNA sequencing (cohort 147 LMS) indicated that patients with low expression of PRKG1 had significantly worse survival. Results indicate that PRKG1 is among the most common altered genes in LMS, and its function is related to cell motility in vitro and tumor aggressiveness in vivo .