The genomic landscape of pediatric Ewing sarcoma.

Brian D Crompton,Amaro Taylor-Weiner,Matthew Defelice,Chip Stewart,Kimberly Stegmaier,Miguel N Rivera,Mariona Suñol,Brendan Blumenstiel,Mark D Fleming,Carmen De Torres,Mara Rosenberg,Sara Seepo,Aaron R Thorner,Angela Schwarz-Cruz Y Celis,Daniel Auclair,Petar Stojanov,Andrey Sivachenko,Michael S Lawrence,Gad Getz,Cinzia Lavarino,Aaron Mckenna,Scott L Carter,Lauren Ambrogio,Sachet A Shukla,Monica L Calicchio,Todd R Golub,Kyle C Kurek,Gabriela Alexe,Jaume Mora,Kristian Cibulskis,Carlos Rodríguez‐Galindo ,Swapnil Mehta ,Iván Imaz-Rosshandler ,Adam Kieżun

doi:10.1158/2159-8290.cd-13-1037

Abstract

Pediatric Ewing sarcoma is characterized by the expression of chimeric fusions of EWS and ETS family transcription factors, representing a paradigm for studying cancers driven by transcription factor rearrangements. In this study, we describe the somatic landscape of pediatric Ewing sarcoma. These tumors are among the most genetically normal cancers characterized to date, with only EWS-ETS rearrangements identified in the majority of tumors. STAG2 loss, however, is present in more than 15% of Ewing sarcoma tumors; occurs by point mutation, rearrangement, and likely nongenetic mechanisms; and is associated with disease dissemination. Perhaps the most striking finding is the paucity of mutations in immediately targetable signal transduction pathways, highlighting the need for new therapeutic approaches to target EWS-ETS fusions in this disease. We performed next-generation sequencing of Ewing sarcoma, a pediatric cancer involving bone, characterized by expression of EWS-ETS fusions. We found remarkably few mutations. However, we discovered that loss of STAG2 expression occurs in 15% of tumors and is associated with metastatic disease, suggesting a potential genetic vulnerability in Ewing sarcoma.

Highlights

F EWS and ETS family transcription factors, representing a paradigm for studying cancers driven by transcription factor rearrangements
Clinical data and demographics were available for a subset of these patients, which were consistent with epidemiologic studies of pediatric Ewing sarcoma
Demographic Male Mean age White Black Axial primary Tumors with EWS–FLI Survival Survival

Summary

Introduction

F EWS and ETS family transcription factors, representing a paradigm for studying cancers driven by transcription factor rearrangements. We describe the somatic landscape of pediatric Ewing sarcoma These tumors are among the most genetically normal cancers characterized to date, with only EWS–ETS rearrangements identified in the majority of tumors. We performed next-generation sequencing of Ewing sarcoma, a pediatric cancer involving bone, characterized by expression of EWS–ETS fusions. The sequencing of cancer genomes in aggressive pediatric solid tumors, such as rhabdoid tumors and retinoblastoma, has revealed remarkably stable genomes [1, 2]. In both cases, oncogenesis is thought, at least in part, to be driven by epigenetic deregulation. We sought to define the genomic landscape of pediatric Ewing sarcoma by integrating multiple next-generation sequencing methods applied to a large panel of human Ewing sarcoma tumors

Methods

Results

Conclusion