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EWSR1 fusion proteins mediate PAX7 expression in Ewing sarcoma
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EWSR1 fusion proteins mediate PAX7 expression in Ewing sarcoma
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Journal Article
EWSR1 fusion proteins mediate PAX7 expression in Ewing sarcoma
2017
Overview
PAX7 is a paired-box transcription factor that is required for the developmental specification of adult skeletal muscle progenitors in mice. We previously demonstrated PAX7 expression as a marker of skeletal muscle differentiation in rhabdomyosarcoma. Here, using analyses of published whole-genome gene expression microarray data, we identify
PAX7
as a gene with significantly increased expression in Ewing sarcoma in comparison to
CIC-DUX4
round cell sarcoma. Analysis of PAX7 in a large cohort of 103 Ewing sarcoma cases by immunohistochemistry revealed expression in 99.0% of cases (102/103).
PAX7
expression was noted in cases demonstrating three distinct Ewing sarcoma
EWSR1
translocations involving
FLI1
,
ERG
, and
NFATc2
. No PAX7 expression was observed in any of 27 cases of
CIC-DUX4
sarcoma by immunohistochemistry (0%; 0/27). Exploring the mechanism of
PAX7
expression in Ewing sarcoma using curated RNA- and ChIP-sequencing data, we demonstrate that the EWSR1 fusion protein is required for
PAX7
expression in Ewing sarcoma and identify a candidate EWSR1-FLI1-bound
PAX7
enhancer that coincides with both a consensus
GGAA
repeat-containing binding site and a peak of regulatory H3K27 acetylation. Taken together, our findings provide mechanistic support for the utility of PAX7 immunohistochemistry in the diagnosis of Ewing sarcoma, while linking this sarcoma of uncertain histogenesis to a key transcriptional regulator of mammalian muscle progenitor cells.
Publisher
Nature Publishing Group US,Elsevier Limited
Subject
/ 45/15
/ 45/61
/ 96/1
/ Biomarkers, Tumor - genetics
/ Biomarkers, Tumor - metabolism
/ Chromatin Assembly and Disassembly
/ Chromatin Immunoprecipitation
/ Gene Expression Regulation, Neoplastic
/ Genomes
/ High-Throughput Nucleotide Sequencing
/ Humans
/ Medicine
/ Oligonucleotide Array Sequence Analysis
/ Oncogene Proteins, Fusion - genetics
/ Oncogene Proteins, Fusion - metabolism
/ PAX7 Transcription Factor - genetics
/ PAX7 Transcription Factor - metabolism
/ RNA
/ RNA-Binding Protein EWS - genetics
