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NIH Research Festival

September 14 – 16, 2016

DNA methylation characterization of fusion-positive and fusion-negative rhabdomyosarcoma primary tumors

Wednesday, September 14, 2016 – Poster Session I
3:00 – 4:30 p.m.

FAES Terrace

NCI

CANCER-8

Authors

  • W Sun
  • B Chatterjee
  • JF Shern
  • S Sindiri
  • Y Wang
  • HS Stevenson
  • DC Edelman
  • PS Meltzer
  • J Khan
  • FG Barr

Abstract

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood and comprises two major subtypes: fusion-positive (FP, most commonly PAX3-FOXO1 or PAX7-FOXO1) and fusion-negative (FN). Our previous study demonstrated that FP and FN RMS tumors exhibit distinct DNA methylation profiles. To further examine the significance of DNA methylation, we generated genome-wide DNA methylation profiles for a new cohort of 48 RMS tumors for which we previously assessed mutation, copy number and expression status. In this new cohort, we confirmed the association of methylation with fusion status in an unsupervised analysis of the most variable probes and in an 11-gene methylation signature developed in our earlier study. Investigation of the RMS subsets defined by methylation clustering revealed a significant association of methylation with PAX3-FOXO1 versus PAX7-FOXO1 in the FP subset, and an association of methylation with RAS mutation status in the FN subset. Localization studies of differentially methylated probes showed that the hypomethylated probes in FP tumors were enriched in the promoter region whereas the hypermethylated probes in FP tumors were enriched in the 3’ UTR region. In our new larger cohort of cases, there was a significant difference in the distribution of PAX3-FOXO1 binding sites between genes with and without differential methylation. Furthermore, genes with both PAX3-FOXO1 binding sites and promoter hypomethylation were usually overexpressed in FP tumors whereas genes with just binding sites or promoter hypomethylation were usually not overexpressed. In conclusion, these results further demonstrate the significance of epigenetic changes in the molecular pathogenesis of RMS.

Scientific Focus Area: Cancer Biology

This page was last updated on Friday, March 26, 2021

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