Genomic profiling identifies genes and pathways dysregulated by HEY1-NCOA2 fusion and shines a light on mesenchymal chondrosarcoma tumorigenesis
Mesenchymal chondrosarcoma is a rare, high-grade, primitive mesenchymal tumor. It accounts for around 2-10% of all chondrosarcomas and mainly affects adolescents and young adults. We previously described the HEY1-NCOA2 as a recurrent gene fusion in mesenchymal chondrosarcoma, an important breakthrough for characterizing this disease; however, little study had been done to characterize the fusion protein functionally, in large part due to a lack of suitable models for evaluating the impact of HEY1-NCOA2 expression in the appropriate cellular context. We used iPSC-derived mesenchymal stem cells (iPSC-MSCs), which can differentiate into chondrocytes, and generated stable transduced iPSC-MSCs with inducible expression of HEY1-NCOA2 fusion protein, wildtype HEY1 or wildtype NCOA2. We next comprehensively analyzed both the DNA binding properties and transcriptional impact of HEY1-NCOA2 expression by integrating genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) and expression profiling (RNA-seq). We demonstrated that HEY1-NCOA2 fusion protein preferentially binds to promoter regions of canonical HEY1 targets, resulting in transactivation of HEY1 targets, and significantly enhances cell proliferation. Intriguingly, we identified that both PDGFB and PDGFRA were directly targeted and upregulated by HEY1-NCOA2; and the fusion protein, but not wildtype HEY1 or NCOA2, dramatically increased the level of phospho-AKT (Ser473). Our findings provide a rationale for exploring PDGF/PI3K/AKT inhibition in treating mesenchymal chondrosarcoma. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Keywords: ChIP-seq; HEY1-NCOA2 fusion; RNA-seq; mesenchymal chondrosarcoma.
© 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Schematic diagrams of HEY1, NCOA2,…
HEY1–NCOA2 fusion protein DNA‐binding pattern…
Gene expression profile associated with…
Functional pathways enriched in HEY1–NCOA2…
HEY1–NCOA2 target gene expression validation.…
HEY1‐NCOA2 significantly increases cell proliferation…
- Identification of a novel, recurrent HEY1-NCOA2 fusion in mesenchymal chondrosarcoma based on a genome-wide screen of exon-level expression data. Wang L, Motoi T, Khanin R, Olshen A, Mertens F, Bridge J, Dal Cin P, Antonescu CR, Singer S, Hameed M, Bovee JV, Hogendoorn PC, Socci N, Ladanyi M.Genes Chromosomes Cancer. 2012 Feb;51(2):127-39. doi: 10.1002/gcc.20937. Epub 2011 Oct 27.PMID: 22034177 Free PMC article.
- Are meningeal hemangiopericytoma and mesenchymal chondrosarcoma the same?: a study of HEY1-NCOA2 fusion. Fritchie KJ, Jin L, Ruano A, Oliveira AM, Rubin BP.Am J Clin Pathol. 2013 Nov;140(5):670-4. doi: 10.1309/AJCPGUNGP52ZSDNS.PMID: 24124145
- Mesenchymal chondrosarcoma diagnosed on FISH for HEY1-NCOA2 fusion gene. Moriya K, Katayama S, Onuma M, Rikiishi T, Hosaka M, Watanabe M, Hasegawa T, Sasahara Y, Kure S.Pediatr Int. 2014 Oct;56(5):e55-7. doi: 10.1111/ped.12407.PMID: 25336010
- Mesenchymal Chondrosarcoma: a Review with Emphasis on its Fusion-Driven Biology. El Beaino M, Roszik J, Livingston JA, Wang WL, Lazar AJ, Amini B, Subbiah V, Lewis V, Conley AP.Curr Oncol Rep. 2018 Mar 26;20(5):37. doi: 10.1007/s11912-018-0668-z.PMID: 29582189 Review.
- Integrating Morphology and Genetics in the Diagnosis of Cartilage Tumors. de Andrea CE, San-Julian M, Bovée JVMG.Surg Pathol Clin. 2017 Sep;10(3):537-552. doi: 10.1016/j.path.2017.04.005.PMID: 28797501 Review.
- Metastatic mesenchymal chondrosarcoma showing a sustained response to cabozantinib: A case report. Blum V, Andrei V, Ameline B, Hofer S, Fuchs B, Strobel K, Allemann A, Bode B, Baumhoer D.Front Oncol. 2022 Dec 12;12:1086677. doi: 10.3389/fonc.2022.1086677. eCollection 2022.PMID: 36578930 Free PMC article.
- Oda Y, Yamamoto H, Kohashi K, et al. Soft tissue sarcomas: from a morphological to a molecular biological approach. Pathol Int 2017; 67: 435–446. – PubMed
- Mertens F, Johansson B, Fioretos T, et al. The emerging complexity of gene fusions in cancer. Nat Rev Cancer 2015; 15: 371–381. – PubMed
- WHO . Classification of Tumours of Soft Tissue and Bone (5th edn). IARC Press: Lyon, 2020.