Characterization of epithelioid sarcoma using massively parallel DNA and RNA sequencing and in vitro models

Epithelioid sarcoma is a soft tissue tumor with an unusual predilection for the distal extremities in young adults. Despite wide-margin resections the 10-year survival is in the range of 50%. The biology of epithelioid sarcoma remains incompletely understood, but one key feature is the loss of SMARCB1. We use whole genome sequencing of five cases of epithelioid sarcoma matched to normal germline DNA, looking for mutations other than SMARCB1. These index cases are supplemented with three additional tumors and three cell lines that undergo whole transcriptome sequencing and are analyzed for somatic point mutations, copy number changes, translocations, and expression patterns. Unlike the situation in other SMARCB1 inactivated tumors, we find a complex genome with a relatively high mutational burden. However, aberrations of SMARCB1 remain the only consistent mutation. Some cases do not show biallelic DNA-level inactivation of this gene which leads us to examine other possible second-hit silencing mechanisms. With the significance attributed to SMARCB1 loss in the genomic landscape of epithelioid sarcoma, we explore two approaches, namely EZH2 and SMARCA4 inhibitions, to specifically exploit this abnormality and suggest novel therapeutic options.Medicine, Faculty ofGraduat