UBC Faculty Research and Publications

The genomic landscape of epithelioid sarcoma cell lines and tumor specimens Jamshidi, Farzad; Bashashati, Ali; Shumansky, Karey; Dickson, Brendan; Gokgoz, Nalan; Wunder, Jay S.; Andrulis, Irene L.; Lazar, Alexander; Shah, Sohrab P.; Huntsman, David G.; Nielsen, Torsten

Abstract

We carried out whole genome and transcriptome sequencing on four tumor/normal pairs of epithelioid sarcoma. These index cases were supplemented with whole transcriptome sequencing of three additional tumors and three cell lines. Unlike in rhabdoid tumors (the other major group of SMARCB1-negative cancers), epithelioid sarcoma shows a complex genome with a higher mutational rate, comparable to that of ovarian carcinomas. Despite this mutational burden, SMARCB1 mutations remain the most recurrent event and are likely critical drivers of tumor formation. Several cases show SMARCB1 alleles that do not go through biallelic inactivation and we explore this further in vitro. Finding CDKN2A deletions in our discovery cohort, we evaluated CDKN2A protein expression in a tissue microarray. 37% (6/16) of cases had lost CDKN2A in greater than or equal to 90% of cells while the remaining cases had maintained the protein. RNAseq based expression analysis of epithelioid sarcoma cell lines shows a unique profile that does not cluster with any particular tissue type nor with other SWI/SNF aberrant lines. The maintenance of expression of most SWI/SNF members other than SMARCB1 prompted us to evaluate protein level expression of other complex members. In vitro studies show that other SWI/SNF proteins are expressed as part of a residual complex, similar to previous observations in rhabdoid tumor lines. This residual SWI/SNF is susceptible to synthetic lethality and may therefore indicate a therapeutic opportunity.

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