Gene co-expression networks restructured gene fusion in rhabdomyosarcoma cancers

Bryan R. Helm, Xiaohui Zhan, Pankita H. Pandya, Mary E. Murray, Karen E. Pollok, Jamie L. Renbarger, Michael J. Ferguson, Zhi Han, Dong Ni, Jie Zhang, Kun Huang

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Rhabdomyosarcoma is subclassified by the presence or absence of a recurrent chromosome translocation that fuses the FOXO1 and PAX3 or PAX7 genes. The fusion protein (FOXO1-PAX3/7) retains both binding domains and becomes a novel and potent transcriptional regulator in rhabdomyosarcoma subtypes. Many studies have characterized and integrated genomic, transcriptomic, and epigenomic differences among rhabdomyosarcoma subtypes that contain the FOXO1-PAX3/7 gene fusion and those that do not; however, few investigations have investigated how gene co-expression networks are altered by FOXO1-PAX3/7. Although transcriptional data offer insight into one level of functional regulation, gene co-expression networks have the potential to identify biological interactions and pathways that underpin oncogenesis and tumorigenicity. Thus, we examined gene co-expression networks for rhabdomyosarcoma that were FOXO1-PAX3 positive, FOXO1-PAX7 positive, or fusion negative. Gene co-expression networks were mined using local maximum Quasi-Clique Merger (lmQCM) and analyzed for co-expression differences among rhabdomyosarcoma subtypes. This analysis observed 41 co-expression modules that were shared between fusion negative and positive samples, of which 17/41 showed significant up- or down-regulation in respect to fusion status. Fusion positive and negative rhabdomyosarcoma showed differing modularity of co-expression networks with fusion negative (n = 109) having significantly more individual modules than fusion positive (n = 53). Subsequent analysis of gene co-expression networks for PAX3 and PAX7 type fusions observed 17/53 were differentially expressed between the two subtypes. Gene list enrichment analysis found that gene ontology terms were poorly matched with biological processes and molecular function for most co-expression modules identified in this study; however, co-expressed modules were frequently localized to cytobands on chromosomes 8 and 11. Overall, we observed substantial restructuring of co-expression networks relative to fusion status and fusion type in rhabdomyosarcoma and identified previously overlooked genes and pathways that may be targeted in this pernicious disease.

Original languageEnglish (US)
Article number665
JournalGenes
Volume10
Issue number9
DOIs
StatePublished - Sep 2019

Keywords

  • Copy number variation
  • Gene co-expression analysis
  • Gene fusion
  • Quasi-clique merger
  • Rhabdomyosarcoma

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Helm, B. R., Zhan, X., Pandya, P. H., Murray, M. E., Pollok, K. E., Renbarger, J. L., Ferguson, M. J., Han, Z., Ni, D., Zhang, J., & Huang, K. (2019). Gene co-expression networks restructured gene fusion in rhabdomyosarcoma cancers. Genes, 10(9), [665]. https://doi.org/10.3390/genes10090665