Abstract 3873: Novel non-genetic mechanisms drive rhabdomyosarcoma tumorigenesis

Abstract

Abstract Most pediatric solid tumors originate from perturbations during development, however the mechanisms that drive these disruptions and promote tumor progression are still poorly understood. We believe that epigenetic deregulation of cancer genes and developmental pathways is a common driver in pediatric cancers, especially those with a low mutation rate. To test this novel idea, we are focusing on rhabdomyosarcoma (RMS), a developing muscle tumor with striking genetic differences between two of the major subtypes. We hypothesize that differential epigenetic deregulation of differentiation programs and cancer genes between the major subtypes are essential for tumorigenesis. Indeed, our preliminary integrative analysis reveal distinct epigenetic landscapes between the two subtypes particularly at the loci of HOX cluster genes A-C, including an oncogenic HOXC long non-coding RNA (lncRNA) called HOTAIR. Knockdown of HOTAIR led to derepression of HOXD10, a candidate tumor suppressor, and a decrease in RMS proliferation, migration, and invasion. Thus, we believe HOX gene deregulation is required for tumorigenesis, and their implication in several adult cancers suggests this currently unappreciated mechanism is likely to be more broadly relevant. In addition, we identified a group of RMS specific novel lncRNAs, of which one demonstrates an essential role in cell survival. Our innovative approach to integrate epigenetic data sets from tumor types with varying genetic differences shed light on the mechanisms that drive tumorigenesis, which may lead to identifying previously unknown potential therapeutic targets. Since current therapeutic options have not changed over the last twenty-five years, these data will especially provide a strong translational impact for children with RMS, whose survival outcomes are less than 20% in the case of metastatic disease. Note: This abstract was not presented at the meeting. Citation Format: Justina McEvoy, Michael Dyer, Xiang Chen. Novel non-genetic mechanisms drive rhabdomyosarcoma tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3873. doi:10.1158/1538-7445.AM2017-3873