Relationship of DNA methylation to mutational changes and transcriptional organization in fusion-positive and fusion-negative rhabdomyosarcoma

Wenyue Sun, Bishwanath Chatterjee, Jack F. Shern, Rajesh Patidar, Young Song, Yonghong Wang, Robert L. Walker, Bruce R. Pawel, Corinne M. Linardic, Peter Houghton, Stephen M. Hewitt, Daniel C. Edelman, Javed Khan, Paul S. Meltzer, Frederic G. Barr

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Our previous study of DNA methylation in the pediatric soft tissue tumor rhabdomyosarcoma (RMS) demonstrated that fusion-positive (FP) and fusion-negative (FN) RMS tumors exhibit distinct DNA methylation patterns. To further examine the significance of DNA methylation differences in RMS, we investigated genome-wide DNA methylation profiles in discovery and validation cohorts. Unsupervised analysis of DNA methylation data identified novel distinct subsets associated with the specific fusion subtype in FP RMS and with RAS mutation status in FN RMS. Furthermore, the methylation pattern in normal muscle is most similar to the FN subset with wild-type RAS mutation status. Several biologically relevant genes were identified with methylation and expression differences between the two fusion subtypes of FP RMS or between the RAS wild-type and mutant subsets of FN RMS. Genomic localization studies showed that promoter and intergenic regions were hypomethylated and the 3′ untranslated regions were hypermethylated in FP compared to FN tumors. There was also a significant difference in the distribution of PAX3-FOXO1 binding sites between genes with and without differential methylation. Moreover, genes with PAX3-FOXO1 binding sites and promoter hypomethylation exhibited the highest frequency of overexpression in FP tumors. Finally, a comparison of RMS model systems revealed that patient-derived xenografts most closely recapitulate the DNA methylation patterns found in human RMS tumors compared to cell lines and cell line-derived xenografts. In conclusion, these findings highlight the interaction of epigenetic changes with mutational alterations and transcriptional organization in RMS tumors, and contribute to improved molecular categorization of these tumors.

Original languageEnglish (US)
Pages (from-to)2707-2717
Number of pages11
JournalInternational Journal of Cancer
Volume144
Issue number11
DOIs
StatePublished - Jun 1 2019

Keywords

  • DNA methylation
  • Rhabdomyosarcoma
  • expression
  • fusion protein
  • xenograft

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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