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

Publication ,  Journal Article
Sun, W; Chatterjee, B; Shern, JF; Patidar, R; Song, Y; Wang, Y; Walker, RL; Pawel, BR; Linardic, CM; Houghton, P; Hewitt, SM; Edelman, DC ...
Published in: Int J Cancer
June 1, 2019

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.

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Published In

Int J Cancer

DOI

EISSN

1097-0215

Publication Date

June 1, 2019

Volume

144

Issue

11

Start / End Page

2707 / 2717

Location

United States

Related Subject Headings

  • ras Proteins
  • Xenograft Model Antitumor Assays
  • Tissue Array Analysis
  • Rhabdomyosarcoma
  • Promoter Regions, Genetic
  • Point Mutation
  • Paired Box Transcription Factors
  • Oncology & Carcinogenesis
  • Oncogene Proteins, Fusion
  • Muscle, Striated
 

Citation

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Sun, W., Chatterjee, B., Shern, J. F., Patidar, R., Song, Y., Wang, Y., … Barr, F. G. (2019). Relationship of DNA methylation to mutational changes and transcriptional organization in fusion-positive and fusion-negative rhabdomyosarcoma. Int J Cancer, 144(11), 2707–2717. https://doi.org/10.1002/ijc.32006
Sun, Wenyue, Bishwanath Chatterjee, Jack F. Shern, Rajesh Patidar, Young Song, Yonghong Wang, Robert L. Walker, et al. “Relationship of DNA methylation to mutational changes and transcriptional organization in fusion-positive and fusion-negative rhabdomyosarcoma.Int J Cancer 144, no. 11 (June 1, 2019): 2707–17. https://doi.org/10.1002/ijc.32006.
Sun W, Chatterjee B, Shern JF, Patidar R, Song Y, Wang Y, et al. Relationship of DNA methylation to mutational changes and transcriptional organization in fusion-positive and fusion-negative rhabdomyosarcoma. Int J Cancer. 2019 Jun 1;144(11):2707–17.
Sun, Wenyue, et al. “Relationship of DNA methylation to mutational changes and transcriptional organization in fusion-positive and fusion-negative rhabdomyosarcoma.Int J Cancer, vol. 144, no. 11, June 2019, pp. 2707–17. Pubmed, doi:10.1002/ijc.32006.
Sun W, Chatterjee B, Shern JF, Patidar R, Song Y, Wang Y, Walker RL, Pawel BR, Linardic CM, Houghton P, Hewitt SM, Edelman DC, Khan J, Meltzer PS, Barr FG. Relationship of DNA methylation to mutational changes and transcriptional organization in fusion-positive and fusion-negative rhabdomyosarcoma. Int J Cancer. 2019 Jun 1;144(11):2707–2717.
Journal cover image

Published In

Int J Cancer

DOI

EISSN

1097-0215

Publication Date

June 1, 2019

Volume

144

Issue

11

Start / End Page

2707 / 2717

Location

United States

Related Subject Headings

  • ras Proteins
  • Xenograft Model Antitumor Assays
  • Tissue Array Analysis
  • Rhabdomyosarcoma
  • Promoter Regions, Genetic
  • Point Mutation
  • Paired Box Transcription Factors
  • Oncology & Carcinogenesis
  • Oncogene Proteins, Fusion
  • Muscle, Striated