Abstract B52: Ewing sarcoma: A case study of clonal aneuploidy and DNA damage repair in pediatric cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2020-07, Vol.80 (14_Supplement), p.B52-B52
• Main Authors: Su, Xiaofeng A., Ma, Duanduan, Parsons, James V., Replogle, John M., Amatruda, James F., Whittaker, Charles A., Stegmaier, Kimberly, Amon, Angelika
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.PEDCA19-B52

Many tumor types harbor specific chromosome gains or losses. In Ewing sarcoma (ES) chromosome 8 gain is extremely common, indicating that this trisomy drives tumorigenesis. However, in primary cells, whole chromosome gains and losses are universally detrimental. We hypothesize that gain of chromosome 8 suppresses cellular stresses associated with oncogenic transformation in ES. In this study, we induced expression of EWS-FLI1 fusion oncogene, which drives ES, in various primary human mesenchymal progenitor and fibroblast cells. We showed that expression of EWS-FLI1 results in a strong cell cycle-dependent replication stress in euploid mesenchymal progenitor cells and fibroblast cells. As a consequence, proliferation is impaired when EWS-FLI1 is expressed in these cells. However, primary fibroblast cells carrying an extra copy of chromosome 8 (trisomy 8) exhibit much less replication stress, and the impairment of proliferation was also not seen in these cells. The levels of replication-associated DNA damage are lower in the trisomy 8 cells than in the euploid cells in the presence of EWS-FLI1. Then, we applied weighted co-expression network analysis (WGCNA) to RNA sequencing data obtained from ES patient tumor tissues in combination of mouse synteny analysis. We identified multiple potential genes and regions on chromosome 8, which are beneficial to ES oncogenesis when gain of extra copies. Above all, we demonstrate that gain of chromosome 8 in Ewing sarcoma facilitates the primary mesenchymal-lineage cells to overcome certain oncogenic stresses and reduces DNA damage associated with tumorigenic processes, which is achieved by cooperative upregulation of multiple gene expression on chromosome 8. Citation Format: Xiaofeng A. Su, Duanduan Ma, James V. Parsons, John M. Replogle, James F. Amatruda, Charles A. Whittaker, Kimberly Stegmaier, Angelika Amon. Ewing sarcoma: A case study of clonal aneuploidy and DNA damage repair in pediatric cancer [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B52.