Abstract IA02: Identity shifts in pediatric cancers

In contrast to adult cancers, most pediatric malignancies display limited genetic heterogeneity. In Ewing sarcoma, the major driver of tumor development is the expression of the chimeric EWSR1-FLI1 transcription factor, which results from a chromosome translocation. Additional recurrent genetic alterations include the CDKN2A, STAG2, and TP53 genes. Through its binding to specific elements including GGAA microsatellite sequences, EWSR1-FLI1 has a major impact on epigenetic landscape of the cancer cells and consequently, obscures the epigenetic makeup of the Ewing cell-of-origin. The Ewing cell is somehow a “neomorphic” cell, the biologic properties of which are tightly dependent upon the expression level of EWSR1-FLI1. When a cell harbors a low level of expression of EWSR1-FLI1, it loses this neomorphic identity and retrieve its cell-of-origin, mesenchymal phenotype. This leads us to propose a new model of phenotypic plasticity whereby the dynamic fluctuation of the expression level of a dominant oncogene is an intrinsic characteristic of its oncogenic potential. The causes of EWSR1-FLI1 expression fluctuations are presently unknown. They may be partly stochastic as they are observed in cell lines in vitro but also dependent upon signals from the surrounding microenvironment. The situation is very different in neuroblastoma where the blueprint of the cell-of-origin, most frequently a noradrenergic progenitor, can be clearly detected whatever the genetic abnormalities of the cancer cells. Our recent data nevertheless suggest that neuroblastoma cells may also exhibit some plasticity and transition between different epigenetic states that witness different cell identities. In conclusion, pediatric cancers constitute simplified cancer systems to investigate the relative and interdependent contributions of genetic and nongenetic factors and to document identity shifts. Citation Format: Olivier Delattre, G.A. Franzetti, K. Laud-Duval, A. Brisac, Valentina Boeva, Caroline Louis-Brennetot, Agathe Peltier, Simon Durand, Cecile Pierre-Eugene, Didier Surdez, Eve Lapouble, Gaelle Pierron, Sandrine Grossetete-Lalami, Isabelle Janoueix-Lerosey. Identity shifts in pediatric cancers [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr IA02.