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.
Highlights
Modules 4 and 9 contained genes related to leukemia and hepatoblastoma and had significant mapping to chromosomes 8 and 11 (Tables 2 and 3, Tables S2 and S3). These results suggest that FOXO1-PAX3/7 positive rhabdomyosarcoma show differential expression for genes that are broadly co-expressed in cancers, perhaps representing core growth and proliferative pathways common to oncogenesis
Prior studies have identified many genes that are differentially regulated with respect the presence or absence of FOXO1-PAX3/7 gene fusion in rhabdomyosarcoma using both experimental and clinical data
Our study importantly rediscovered differential regulation of key apoptotic genes among co-expressed modules that have been previously targeted by pharmaceutical development for rhabdomyosarcoma, though existing literature is limited
Summary
Gene fusion is an important consequence of mutation that has been observed in many cancers including malignant solid tumors, leukemia, and especially pediatric sarcoma [1,2]; such fusions may be drivers of, or contribute to cancer progression. Recent studies have underscored the important functional roles of gene fusions in sarcoma biology with the promise of providing insights that lead to treatment and improved prognosis. Rhabdomyosarcoma frequently contain recurrent gene fusions involving FOXO1 genes and PAX genes amid a changing landscape of genome mutations and structural variations [3]. The goal of this paper is to implement a systems biology approach for the FOXO1-PAX3/7 fusion in rhabdomyosarcoma using gene correlation network analysis to infer novel biological insights and hypotheses about this aggressive pediatric cancer
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