title: Fusion transcriptome profiling provides insights into alveolar rhabdomyosarcoma.
abstract: Gene fusions and fusion products were thought to be unique features of neoplasia. However, more and more studies have identified fusion RNAs in normal physiology. Through RNA sequencing of 27 human noncancer tissues, a large number of fusion RNAs were found. By analyzing fusion transcriptome, we observed close clusterings between samples of same or similar tissues, supporting the feasibility of using fusion RNA profiling to reveal connections between biological samples. To put the concept into use, we selected alveolar rhabdomyosarcoma (ARMS), a myogenic pediatric cancer whose exact cell of origin is not clear. PAX3-FOXO1 (paired box gene 3 fused with forkhead box O1) fusion RNA, which is considered a hallmark of ARMS, was recently found during normal muscle cell differentiation. We performed and analyzed RNA sequencing from various time points during myogenesis and uncovered many chimeric fusion RNAs. Interestingly, we found that the fusion RNA profile of RH30, an ARMS cell line, is most similar to the myogenesis time point when PAX3-FOXO1 is expressed. In contrast, full transcriptome clustering analysis failed to uncover this connection. Strikingly, all of the 18 chimeric RNAs in RH30 cells could be detected at the same myogenic time point(s). In addition, the seven chimeric RNAs that follow the exact transient expression pattern as PAX3-FOXO1 are specific to rhabdomyosarcoma cells. Further testing with clinical samples also confirmed their specificity to rhabdomyosarcoma. These results provide further support for the link between at least some ARMSs and the PAX3-FOXO1-expressing myogenic cells and demonstrate that fusion RNA profiling can be used to investigate the etiology of fusion-gene-associated cancers.
authors: Department of Pathology, University of Virginia, Charlottesville, VA 22908.
authors: Zhongqiu
authors: Z
authors: Xie
authors: Department of Pathology, University of Virginia, Charlottesville, VA 22908.
authors: Mihaela
authors: M
authors: Babiceanu
authors: Department of Pathology, University of Virginia, Charlottesville, VA 22908.
authors: Shailesh
authors: S
authors: Kumar
authors: Department of Pathology, University of Virginia, Charlottesville, VA 22908.
authors: Yuemeng
authors: Y
authors: Jia
authors: Department of Pathology, University of Virginia, Charlottesville, VA 22908.
authors: Fujun
authors: F
authors: Qin
authors: Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892.
authors: Frederic G
authors: FG
authors: Barr
authors: Department of Pathology, University of Virginia, Charlottesville, VA 22908; hl9r@virginia.edu.|University of Virginia Cancer Center, Charlottesville, VA 22908.
authors: Hui
authors: H
authors: Li
mesh_terms: D045744:Cell Line, Tumor; D000071161:Forkhead Box Protein O1 / Q000235:genetics; D020869:Gene Expression Profiling; D050939:Gene Fusion; D006801:Humans; D059630:Mesenchymal Stem Cells; D024510:Muscle Development / Q000235:genetics; D000072041:PAX3 Transcription Factor / Q000235:genetics; D012313:RNA / Q000235:genetics*; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics*; D017423:Sequence Analysis, RNA
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D012313:RNA
keywords: PAX3-FOXO1; chimeric RNA; gene fusion; myogenesis; rhabdomyosarcoma