Undifferentiated small round cell sarcomas (SRCSs) of bone and soft tissue comprise a heterogeneous group of highly aggressive tumours associated with a poor prognosis, especially in metastatic disease. SRCS entities mainly occur in the third decade of life and can exhibit striking disparities regarding preferentially affected sex and tumour localization. SRCSs comprise new entities defined by specific genetic abnormalities, namely EWSR1–non-ETS fusions, CIC-rearrangements or BCOR genetic alterations, as well as EWSR1–ETS fusions in the prototypic SRCS Ewing sarcoma. These gene fusions mainly encode aberrant oncogenic transcription factors that massively rewire the transcriptome and epigenome of the as yet unknown cell or cells of origin. Additional mutations or copy number variants are rare at diagnosis and, depending on the tumour entity, may involve TP53, CDKN2A and others. Histologically, these lesions consist of small round cells expressing variable levels of CD99 and specific marker proteins, including cyclin B3, ETV4, WT1, NKX3-1 and aggrecan, depending on the entity. Besides locoregional treatment that should follow standard protocols for sarcoma management, (neo)adjuvant treatment is as yet ill-defined but generally follows that of Ewing sarcoma and is associated with adverse effects that might compromise quality of life. Emerging studies on the molecular mechanisms of SRCSs and the development of genetically engineered animal models hold promise for improvements in early detection, disease monitoring, treatment-related toxicity, overall survival and quality of life.
This is a preview of subscription content, access via your institution
Subscribe to Nature+
Get immediate online access to Nature and 55 other Nature journal
Subscribe to Journal
Get full journal access for 1 year
only $79.00 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Antonescu, C. Round cell sarcomas beyond Ewing: emerging entities. Histopathology 64, 26–37 (2014).
Sbaraglia, M., Bellan, E. & Dei Tos, A. P. The 2020 WHO classification of soft tissue tumours: news and perspectives. Pathologica 113, 70–84 (2021).
Maki, R. G., Grohar, P. J. & Antonescu, C. R. Ewing sarcoma and related FET family translocation-associated round cell tumors: a century of clinical and scientific progress. Genes Chromosomes Cancer https://doi.org/10.1002/gcc.23050 (2022).
Dickson, B. C. Undifferentiated small round cell sarcomas of bone. Surg. Pathol. Clin. 14, 679–694 (2021).
Carter, C. S. & Patel, R. M. Important recently characterized non-Ewing small round cell tumors. Surg. Pathol. Clin. 12, 191–215 (2019).
Miettinen, M. et al. New fusion sarcomas: histopathology and clinical significance of selected entities. Hum. Pathol. 86, 57–65 (2019).
Grünewald, T. G. P. et al. Ewing sarcoma. Nat. Rev. Dis. Primers 4, 5 (2018).
Gerald, W. L. & Haber, D. A. The EWS-WT1 gene fusion in desmoplastic small round cell tumor. Semin. Cancer Biol. 15, 197–205 (2005).
Pierron, G. et al. A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat. Genet. 44, 461–466 (2012). This paper describes for the first time BCOR–CCNB3 sarcomas as biologically distinct from Ewing sarcoma.
Koelsche, C. et al. DNA methylation profiling distinguishes Ewing-like sarcoma with EWSR1-NFATc2 fusion from Ewing sarcoma. J. Cancer Res. Clin. Oncol. 145, 1273–1281 (2019).
Koelsche, C. et al. Array-based DNA-methylation profiling in sarcomas with small blue round cell histology provides valuable diagnostic information. Mod. Pathol. 31, 1246–1256 (2018).
Antonescu, C. R. et al. Sarcomas with CIC-rearrangements are a distinct pathologic entity with aggressive outcome: a clinicopathologic and molecular study of 115 cases. Am. J. Surg. Pathol. 41, 941–949 (2017). This paper describes for the first time CIC-rearranged sarcomas as distinct entities from other mimics such as Ewing sarcoma.
Baldauf, M. C. et al. Robust diagnosis of Ewing sarcoma by immunohistochemical detection of super-enhancer-driven EWSR1-ETS targets. Oncotarget 9, 1587–1601 (2018).
Watson, S. et al. Transcriptomic definition of molecular subgroups of small round cell sarcomas. J. Pathol. 245, 29–40 (2018). This paper combines the unbiased identification of gene fusions with unsupervised gene expression analyses to identify biologically homogeneous groups of tumours including CIC-rearranged, BCOR-rearranged and EWSR1–NFATC2 or FUS–NFATC2 sarcomas.
Kallen, M. E. & Hornick, J. L. The 2020 WHO classification: what’s new in soft tissue tumor pathology? Am. J. Surg. Pathol. 45, e1–e23 (2021).
WHO Classification of Tumours Editorial Board. Soft Tissue and Bone Tumours: WHO Classification of Tumours 5th edn Vol. 3 (IARC Press, 2020).
Gerald, W. L. & Rosai, J. Case 2. Desmoplastic small cell tumor with divergent differentiation. Pediatr. Pathol. 9, 177–183 (1989). This paper is the first description of a DSRCT.
Delattre, O. et al. The Ewing family of tumors–a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N. Engl. J. Med. 331, 294–299 (1994).
Koelsche, C. et al. Sarcoma classification by DNA methylation profiling. Nat. Commun. 12, 498 (2021). In this paper, methylation profiling demonstrates independent clustering of BCOR-rearranged sarcomas, CIC-rearranged sarcomas and Ewing sarcoma, highlighting their distinct nature.
Lettieri, C. K., Garcia-Filion, P. & Hingorani, P. Incidence and outcomes of desmoplastic small round cell tumor: results from the Surveillance, Epidemiology, and End Results database. J. Cancer Epidemiol. 2014, 680126 (2014).
de Pinieux, G. et al. Nationwide incidence of sarcomas and connective tissue tumors of intermediate malignancy over four years using an expert pathology review network. PLoS ONE 16, e0246958 (2021). This paper contains the most solid epidemiological information for SRCSs to date.
Worch, J. et al. Racial differences in the incidence of mesenchymal tumors associated with EWSR1 translocation. Cancer Epidemiol. Biomark. Prev. 20, 449–453 (2011).
Wong, H. H. et al. Desmoplastic small round cell tumour: characteristics and prognostic factors of 41 patients and review of the literature. Clin. Sarcoma Res. 3, 14 (2013).
Honoré, C. et al. Can we cure patients with abdominal desmoplastic small round cell tumor? Results of a retrospective multicentric study on 100 patients. Surg. Oncol. 29, 107–112 (2019).
Honoré, C. et al. Abdominal desmoplastic small round cell tumor: multimodal treatment combining chemotherapy, surgery, and radiotherapy is the best option. Ann. Surg. Oncol. 22, 1073–1079 (2015).
Lal, D. R. et al. Results of multimodal treatment for desmoplastic small round cell tumors. J. Pediatr. Surg. 40, 251–255 (2005).
Romeo, S. et al. Malignant fibrous histiocytoma and fibrosarcoma of bone: a re-assessment in the light of currently employed morphological, immunohistochemical and molecular approaches. Virchows Arch. 461, 561–570 (2012).
Wang, W.-L. et al. Expression of ERG, an Ets family transcription factor, identifies ERG-rearranged Ewing sarcoma. Mod. Pathol. 25, 1378–1383 (2012).
Szuhai, K. et al. The NFATc2 gene is involved in a novel cloned translocation in a Ewing sarcoma variant that couples its function in immunology to oncology. Clin. Cancer Res. 15, 2259–2268 (2009). This paper is the first description of the EWSR1–NFATC2 fusion.
Wang, G. Y. et al. EWSR1-NFATC2 translocation-associated sarcoma clinicopathologic findings in a rare aggressive primary bone or soft tissue tumor. Am. J. Surg. Pathol. 43, 1112–1122 (2019).
Cohen, J. N. et al. EWSR1-NFATC2 gene fusion in a soft tissue tumor with epithelioid round cell morphology and abundant stroma: a case report and review of the literature. Hum. Pathol. 81, 281–290 (2018).
Yoshida, A. et al. CIC-rearranged sarcomas: a study of 20 cases and comparisons with Ewing sarcomas. Am. J. Surg. Pathol. 40, 313–323 (2016).
Italiano, A. et al. High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1-negative undifferentiated small blue round cell sarcomas. Genes Chromosomes Cancer 51, 207–218 (2012).
Cohen-Gogo, S. et al. Ewing-like sarcomas with BCOR-CCNB3 fusion transcript: a clinical, radiological and pathological retrospective study from the Société Française des Cancers de L’Enfant. Pediatr. Blood Cancer 61, 2191–2198 (2014).
Peters, T. L. et al. BCOR-CCNB3 fusions are frequent in undifferentiated sarcomas of male children. Mod. Pathol. 28, 575–586 (2015).
Puls, F. et al. BCOR-CCNB3 (Ewing-like) sarcoma: a clinicopathologic analysis of 10 cases, in comparison with conventional Ewing sarcoma. Am. J. Surg. Pathol. 38, 1307–1318 (2014).
Kyriazoglou, A. & Bagos, P. Meta-analysis of BCOR rearranged sarcomas: challenging the therapeutic approach. Acta Oncol. 60, 721–726 (2021).
Postel-Vinay, S. et al. Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma. Nat. Genet. 44, 323–327 (2012).
Grünewald, T. G. P. et al. Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite. Nat. Genet. 47, 1073–1078 (2015).
Ballinger, M. L. et al. Monogenic and polygenic determinants of sarcoma risk: an international genetic study. Lancet Oncol. 17, 1261–1271 (2016).
Lin, S.-H. et al. Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma. PLoS ONE 15, e0237792 (2020).
Gillani, R. et al. Germline predisposition to pediatric Ewing sarcoma is characterized by inherited pathogenic variants in DNA damage repair genes. Am. J. Hum. Genet. 109, 1026–1037 (2022).
Kim, J., Lee, K. & Pelletier, J. The desmoplastic small round cell tumor t(11;22) translocation produces EWS/WT1 isoforms with differing oncogenic properties. Oncogene 16, 1973–1979 (1998).
Murphy, A. J. et al. A new molecular variant of desmoplastic small round cell tumor: significance of WT1 immunostaining in this entity. Hum. Pathol. 39, 1763–1770 (2008).
Reynolds, P. A. et al. Identification of a DNA-binding site and transcriptional target for the EWS-WT1(+KTS) oncoprotein. Genes Dev. 17, 2094–2107 (2003).
Kyriazoglou, A. et al. A case series of BCOR sarcomas with a new splice variant of BCOR/CCNB3 fusion gene. In Vivo 34, 2947–2954 (2020).
Tirode, F. et al. Mesenchymal stem cell features of Ewing tumors. Cancer Cell 11, 421–429 (2007).
Tanaka, M. et al. Ewing’s sarcoma precursors are highly enriched in embryonic osteochondrogenic progenitors. J. Clin. Invest. 124, 3061–3074 (2014).
Sole, A. et al. Unraveling Ewing sarcoma tumorigenesis originating from patient-derived mesenchymal stem cells. Cancer Res. 81, 4994–5006 (2021).
Surdez, D. et al. STAG2 mutations alter CTCF-anchored loop extrusion, reduce cis-regulatory interactions and EWSR1-FLI1 activity in Ewing sarcoma. Cancer Cell 39, 810–826.e9 (2021).
Lessnick, S. L., Dacwag, C. S. & Golub, T. R. The Ewing’s sarcoma oncoprotein EWS/FLI induces a p53-dependent growth arrest in primary human fibroblasts. Cancer Cell 1, 393–401 (2002).
Kang, H.-J. et al. EWS-WT1 oncoprotein activates neuronal reprogramming factor ASCL1 and promotes neural differentiation. Cancer Res. 74, 4526–4535 (2014).
Kawamura-Saito, M. et al. Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation. Hum. Mol. Genet. 15, 2125–2137 (2006).
Yoshimoto, T. et al. CIC-DUX4 induces small round cell sarcomas distinct from Ewing sarcoma. Cancer Res. 77, 2927–2937 (2017).
Yamada, Y. et al. Histological and immunohistochemical characteristics of undifferentiated small round cell sarcomas associated with CIC-DUX4 and BCOR-CCNB3 fusion genes. Virchows Arch. 470, 373–380 (2017).
Kao, Y.-C. et al. BCOR-CCNB3 fusion positive sarcomas: a clinicopathologic and molecular analysis of 36 cases with comparison to morphologic spectrum and clinical behavior of other round cell sarcomas. Am. J. Surg. Pathol. 42, 604–615 (2018).
Sbaraglia, M., Righi, A., Gambarotti, M. & Dei Tos, A. P. Ewing sarcoma and Ewing-like tumors. Virchows Arch. 476, 109–119 (2020).
Roy, A. et al. Recurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney. Nat. Commun. 6, 8891 (2015).
Ueno-Yokohata, H. et al. Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney. Nat. Genet. 47, 861–863 (2015).
Hoang, L. N. et al. Novel high-grade endometrial stromal sarcoma: a morphologic mimicker of myxoid leiomyosarcoma. Am. J. Surg. Pathol. 41, 12–24 (2017).
Antonescu, C. R. et al. Novel ZC3H7B-BCOR, MEAF6-PHF1, and EPC1-PHF1 fusions in ossifying fibromyxoid tumors–molecular characterization shows genetic overlap with endometrial stromal sarcoma. Genes Chromosomes Cancer 53, 183–193 (2014).
Kao, Y.-C. et al. Recurrent BCOR internal tandem duplication and YWHAE-NUTM2B fusions in soft tissue undifferentiated round cell sarcoma of infancy: overlapping genetic features with clear cell sarcoma of kidney. Am. J. Surg. Pathol. 40, 1009–1020 (2016).
Santiago, T., Clay, M. R., Allen, S. J. & Orr, B. A. Recurrent BCOR internal tandem duplication and BCOR or BCL6 expression distinguish primitive myxoid mesenchymal tumor of infancy from congenital infantile fibrosarcoma. Mod. Pathol. 30, 884–891 (2017).
Sturm, D. et al. New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 164, 1060–1072 (2016).
Bouchoucha, Y. et al. Intra- and extra-cranial BCOR-ITD tumours are separate entities within the BCOR-rearranged family. J. Pathol. Clin. Res. 8, 217–232 (2022).
Ladanyi, M. & Gerald, W. Fusion of the EWS and WT1 genes in the desmoplastic small round cell tumor. Cancer Res. 54, 2837–2840 (1994). This paper is the first description of the EWSR1–WT1 fusion in DSRCT.
Schoolmeester, J. K. et al. EWSR1-WT1 gene fusions in neoplasms other than desmoplastic small round cell tumor: a report of three unusual tumors involving the female genital tract and review of the literature. Mod. Pathol. 34, 1912–1920 (2021).
Pižem, J. et al. FUS-NFATC2 or EWSR1-NFATC2 fusions are present in a large proportion of simple bone cysts. Am. J. Surg. Pathol. 44, 1623–1634 (2020).
Mastrangelo, T. et al. A novel zinc finger gene is fused to EWS in small round cell tumor. Oncogene 19, 3799–3804 (2000).
Bridge, J. A. et al. Clinical, pathological, and genomic features of EWSR1-PATZ1 fusion sarcoma. Mod. Pathol. 32, 1593–1604 (2019).
Siegfried, A. et al. EWSR1-PATZ1 gene fusion may define a new glioneuronal tumor entity. Brain Pathol. 29, 53–62 (2019).
Lopez-Nunez, O. et al. The spectrum of rare central nervous system (CNS) tumors with EWSR1-non-ETS fusions: experience from three pediatric institutions with review of the literature. Brain Pathol. 31, 70–83 (2021).
Al-Obaidy, K. I. et al. EWSR1-PATZ1 fusion renal cell carcinoma: a recurrent gene fusion characterizing thyroid-like follicular renal cell carcinoma. Mod. Pathol. 34, 1921–1934 (2021).
Antonescu, C. R. et al. EWSR1-POU5F1 fusion in soft tissue myoepithelial tumors. A molecular analysis of sixty-six cases, including soft tissue, bone, and visceral lesions, showing common involvement of the EWSR1 gene. Genes Chromosomes Cancer 49, 1114–1124 (2010).
Huang, S.-C. et al. Novel FUS-KLF17 and EWSR1-KLF17 fusions in myoepithelial tumors. Genes Chromosomes Cancer 54, 267–275 (2015).
Agaram, N. P. et al. EWSR1-PBX3: a novel gene fusion in myoepithelial tumors. Genes Chromosomes Cancer 54, 63–71 (2015).
Jiao, Y. et al. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget 3, 709–722 (2012).
Yamamoto, Y., Abe, A. & Emi, N. Clarifying the impact of polycomb complex component disruption in human cancers. Mol. Cancer Res. 12, 479–484 (2014).
Bettegowda, C. et al. Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science 333, 1453–1455 (2011).
Sugita, S. et al. NUTM2A-CIC fusion small round cell sarcoma: a genetically distinct variant of CIC-rearranged sarcoma. Hum. Pathol. 65, 225–230 (2017).
Huang, S.-C. et al. Recurrent CIC gene abnormalities in angiosarcomas: a molecular study of 120 cases with concurrent investigation of PLCG1, KDR, MYC, and FLT4 gene alterations. Am. J. Surg. Pathol. 40, 645–655 (2016).
Brohl, A. S. et al. The genomic landscape of the Ewing sarcoma family of tumors reveals recurrent STAG2 mutation. PLoS Genet. 10, e1004475 (2014).
Specht, K. et al. Novel BCOR-MAML3 and ZC3H7B-BCOR gene fusions in undifferentiated small blue round cell sarcomas. Am. J. Surg. Pathol. 40, 433–442 (2016).
Panagopoulos, I. et al. Fusion of the ZC3H7B and BCOR genes in endometrial stromal sarcomas carrying an X;22-translocation. Genes Chromosomes Cancer 52, 610–618 (2013).
Kao, Y.-C. et al. NTRK3 overexpression in undifferentiated sarcomas with YWHAE and BCOR genetic alterations. Mod. Pathol. 33, 1341–1349 (2020).
Yoshida, A. et al. Expanding the clinicopathologic and molecular spectrum of BCOR-associated sarcomas in adults. Histopathology 76, 509–520 (2020).
Aldera, A. P. & Govender, D. Gene of the month: BCOR. J. Clin. Pathol. 73, 314–317 (2020).
Oliveira, A. M. et al. Extraskeletal myxoid chondrosarcoma: a clinicopathologic, immunohistochemical, and ploidy analysis of 23 cases. Mod. Pathol. 13, 900–908 (2000).
Antonescu, C. R. et al. Specificity of TLS-CHOP rearrangement for classic myxoid/round cell liposarcoma. J. Mol. Diagn. 2, 132–138 (2000).
Wang, L. et al. Identification of a novel, recurrent HEY1-NCOA2 fusion in mesenchymal chondrosarcoma based on a genome-wide screen of exon-level expression data. Genes Chromosomes Cancer 51, 127–139 (2012).
Karlsson, J., Valind, A. & Gisselsson, D. BCOR internal tandem duplication and YWHAE-NUTM2B/E fusion are mutually exclusive events in clear cell sarcoma of the kidney. Genes Chromosomes Cancer 55, 120–123 (2016).
Alholle, A. et al. Genetic analyses of undifferentiated small round cell sarcoma identifies a novel sarcoma subtype with a recurrent CRTC1-SS18 gene fusion. J. Pathol. 245, 186–196 (2018).
Antonescu, C. R., Agaram, N. P., Sung, Y.-S., Zhang, L. & Dickson, B. C. Undifferentiated round cell sarcomas with novel SS18-POU5F1 fusions. Genes Chromosomes Cancer 59, 620–626 (2020).
Diolaiti, D. et al. A recurrent novel MGA-NUTM1 fusion identifies a new subtype of high-grade spindle cell sarcoma. Cold Spring Harb. Mol. Case Stud. 4, a003194 (2018).
Dickson, B. C. et al. NUTM1 gene fusions characterize a subset of undifferentiated soft tissue and visceral tumors. Am. J. Surg. Pathol. 42, 636–645 (2018).
Seligson, N. D. et al. Multiscale-omic assessment of EWSR1-NFATc2 fusion positive sarcomas identifies the mTOR pathway as a potential therapeutic target. NPJ Precis. Oncol. 5, 43 (2021).
Mangray, S. et al. Clinicopathologic features of a series of primary renal CIC-rearranged sarcomas with comprehensive molecular analysis. Am. J. Surg. Pathol. 42, 1360–1369 (2018).
Le Loarer, F. et al. Advances in the classification of round cell sarcomas. Histopathology 80, 33–53 (2022).
Slotkin, E. K. et al. Comprehensive molecular profiling of desmoplastic small round cell tumor. Mol. Cancer Res. 19, 1146–1155 (2021).
Wu, C.-C. et al. Multi-site desmoplastic small round cell tumors are genetically related and immune-cold. NPJ Precis. Oncol. 6, 21 (2022).
Devecchi, A. et al. The genomics of desmoplastic small round cell tumor reveals the deregulation of genes related to DNA damage response, epithelial-mesenchymal transition, and immune response. Cancer Commun. 38, 70 (2018).
Chow, W. A. et al. Recurrent secondary genomic alterations in desmoplastic small round cell tumors. BMC Med. Genet. 21, 101 (2020).
Sydow, S. et al. Genomic and transcriptomic characterization of desmoplastic small round cell tumors. Genes Chromosomes Cancer 60, 595–603 (2021).
Perret, R. et al. NFATc2-rearranged sarcomas: clinicopathologic, molecular, and cytogenetic study of 7 cases with evidence of AGGRECAN as a novel diagnostic marker. Mod. Pathol. 33, 1930–1944 (2020).
Nacev, B. A. et al. The epigenomics of sarcoma. Nat. Rev. Cancer 20, 608–623 (2020).
Nacev, B. A. et al. The expanding landscape of ‘oncohistone’ mutations in human cancers. Nature 567, 473–478 (2019).
Arimura, Y. et al. Cancer-associated mutations of histones H2B, H3.1 and H2A.Z.1 affect the structure and stability of the nucleosome. Nucleic Acids Res. 46, 10007–10018 (2018).
Soon, G. S. & Petersson, F. Beware of immunohistochemistry–report of a cytokeratin-, desmin- and INI-1-negative pelvic desmoplastic small round cell tumor in a 51 year old woman. Int. J. Clin. Exp. Pathol. 8, 973–982 (2015).
Lu, C. & Allis, C. D. SWI/SNF complex in cancer. Nat. Genet. 49, 178–179 (2017).
Nakayama, R. T. et al. SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters. Nat. Genet. 49, 1613–1623 (2017).
Kohashi, K. & Oda, Y. Oncogenic roles of SMARCB1/INI1 and its deficient tumors. Cancer Sci. 108, 547–552 (2017).
Lindén, M. et al. FET family fusion oncoproteins target the SWI/SNF chromatin remodeling complex. EMBO Rep. 20, e45766 (2019).
Tomazou, E. M. et al. Epigenome mapping reveals distinct modes of gene regulation and widespread enhancer reprogramming by the oncogenic fusion protein EWS-FLI1. Cell Rep. 10, 1082–1095 (2015).
Sheffield, N. C. et al. DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma. Nat. Med. 23, 386–395 (2017).
Fan, Z. et al. BCOR regulates mesenchymal stem cell function by epigenetic mechanisms. Nat. Cell Biol. 11, 1002–1009 (2009).
Bosnakovski, D. et al. Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma. Oncogenesis 10, 68 (2021).
Choi, S. H. et al. DUX4 recruits p300/CBP through its C-terminus and induces global H3K27 acetylation changes. Nucleic Acids Res. 44, 5161–5173 (2016).
Bosnakovski, D. et al. A novel P300 inhibitor reverses DUX4-mediated global histone H3 hyperacetylation, target gene expression, and cell death. Sci. Adv. 5, eaaw7781 (2019).
Okimoto, R. A. et al. CIC-DUX4 oncoprotein drives sarcoma metastasis and tumorigenesis via distinct regulatory programs. J. Clin. Invest. 129, 3401–3406 (2019).
Okimoto, R. A. et al. Inactivation of Capicua drives cancer metastasis. Nat. Genet. 49, 87–96 (2017).
Le Guellec, S. et al. ETV4 is a useful marker for the diagnosis of CIC-rearranged undifferentiated round-cell sarcomas: a study of 127 cases including mimicking lesions. Mod. Pathol. 29, 1523–1531 (2016).
Nakai, S. et al. Establishment of a novel human CIC-DUX4 sarcoma cell line, Kitra-SRS, with autocrine IGF-1R activation and metastatic potential to the lungs. Sci. Rep. 9, 15812 (2019).
Carrabotta, M. et al. Integrated molecular characterization of patient-derived models reveals therapeutic strategies for treating CIC-DUX4 sarcoma. Cancer Res. 82, 708–720 (2022). This paper reveals a CIC–DUX4 sarcoma-specific signature that differentiates these sarcomas from other fusion-driven sarcomas, and proposes a therapeutic strategy based on AKT–mTOR inhibition.
Gedminas, J. M. et al. Desmoplastic small round cell tumor is dependent on the EWS-WT1 transcription factor. Oncogenesis 9, 41 (2020).
Grünewald, T. G. et al. Sarcoma treatment in the era of molecular medicine. EMBO Mol. Med. https://doi.org/10.15252/emmm.201911131 (2020).
Brady, E. J., Hameed, M., Tap, W. D. & Hwang, S. Imaging features and clinical course of undifferentiated round cell sarcomas with CIC-DUX4 and BCOR-CCNB3 translocations. Skelet. Radiol. 50, 521–529 (2021).
Kim, E. et al. Capicua suppresses hepatocellular carcinoma progression by controlling the ETV4-MMP1 axis. Hepatology 67, 2287–2301 (2018).
Adsay, V., Cheng, J., Athanasian, E., Gerald, W. & Rosai, J. Primary desmoplastic small cell tumor of soft tissues and bone of the hand. Am. J. Surg. Pathol. 23, 1408–1413 (1999).
Markides, C. S. A. et al. Desmoplastic small round cell tumor (DSRCT) xenografts and tissue culture lines: establishment and initial characterization. Oncol. Lett. 5, 1453–1456 (2013).
Grunewald, T. G. P. et al. STEAP1 is associated with the invasive and oxidative stress phenotype of Ewing tumors. Mol. Cancer Res. 10, 52–65 (2012).
Miller, I. V. et al. First identification of Ewing’s sarcoma-derived extracellular vesicles and exploration of their biological and potential diagnostic implications. Biol. Cell 105, 289–303 (2013).
Ventura, S. et al. CD99 regulates neural differentiation of Ewing sarcoma cells through miR-34a-Notch-mediated control of NF-κB signaling. Oncogene 35, 3944–3954 (2016).
Fong, E. L. S. et al. Modeling Ewing sarcoma tumors in vitro with 3D scaffolds. Proc. Natl Acad. Sci. USA 110, 6500–6505 (2013).
Santoro, M., Lamhamedi-Cherradi, S.-E., Menegaz, B. A., Ludwig, J. A. & Mikos, A. G. Flow perfusion effects on three-dimensional culture and drug sensitivity of Ewing sarcoma. Proc. Natl Acad. Sci. USA 112, 10304–10309 (2015).
Villasante, A. et al. Recapitulating the size and cargo of tumor exosomes in a tissue-engineered model. Theranostics 6, 1119–1130 (2016).
Komatsu, A. et al. The CAM model for CIC-DUX4 sarcoma and its potential use for precision medicine. Cells 10, 2613 (2021).
Li, H. et al. Adenosine transporter ENT4 is a direct target of EWS/WT1 translocation product and is highly expressed in desmoplastic small round cell tumor. PLoS ONE 3, e2353 (2008).
Petitprez, F. et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 577, 556–560 (2020).
Orth, M. F. et al. A comparative view on the expression patterns of PD-L1 and PD-1 in soft tissue sarcomas. Cancer Immunol. Immunother. 69, 1353–1362 (2020).
Ren, E.-H. et al. An immune-related gene signature for determining Ewing sarcoma prognosis based on machine learning. J. Cancer Res. Clin. Oncol. 147, 153–165 (2021).
Brohl, A. S. et al. Immuno-transcriptomic profiling of extracranial pediatric solid malignancies. Cell Rep. 37, 110047 (2021).
Hingorani, P. et al. Transcriptome analysis of desmoplastic small round cell tumors identifies actionable therapeutic targets: a report from the Children’s Oncology Group. Sci. Rep. 10, 12318 (2020).
Blaney, S. M., Helman, L. J. & Adamson, P. C. Pizzo & Poplack’s Pediatric Oncology (Lippincott Williams & Wilkins, 2020).
Ko, J. S. et al. Superficial sarcomas with CIC rearrangement are aggressive neoplasms: a series of eight cases. J. Cutan. Pathol. 47, 509–516 (2020).
Maloney, N. et al. Expanding the differential of superficial tumors with round-cell morphology: report of three cases of CIC-rearranged sarcoma, a potentially under-recognized entity. J. Cutan. Pathol. 47, 535–540 (2020).
Widhe, B. & Widhe, T. Initial symptoms and clinical features in osteosarcoma and Ewing sarcoma. J. Bone Jt. Surg. Am. 82, 667–674 (2000).
Alonso, L., Navarro-Perez, V., Sanchez-Muñoz, A. & Alba, E. Time to diagnosis of Ewing tumors in children and adolescents is not associated with metastasis or survival. J. Clin. Oncol. 32, 4020 (2014).
Gerald, W. L. et al. Clinical, pathologic, and molecular spectrum of tumors associated with t(11;22)(p13;q12): desmoplastic small round-cell tumor and its variants. J. Clin. Oncol. 16, 3028–3036 (1998).
Lee, Y.-S. & Hsiao, C.-H. Desmoplastic small round cell tumor: a clinicopathologic, immunohistochemical and molecular study of four patients. J. Formos. Med. Assoc. 106, 854–860 (2007).
Campos, F. et al. Clinical characteristics, management, and outcomes of 19 nonpediatric patients with desmoplastic small round cell tumor: a cohort of Brazilian patients. Sarcoma 2020, 8713165 (2020).
Angarita, F. A. et al. Clinical features and outcomes of 20 patients with abdominopelvic desmoplastic small round cell tumor. Eur. J. Surg. Oncol. 43, 423–431 (2017).
Wei, G. et al. Intra-abdominal desmoplastic small round cell tumor: current treatment options and perspectives. Front. Oncol. 11, 705760 (2021).
Subbiah, V. et al. Multimodality treatment of desmoplastic small round cell tumor: chemotherapy and complete cytoreductive surgery improve patient survival. Clin. Cancer Res. 24, 4865–4873 (2018).
Hayes-Jordan, A., LaQuaglia, M. P. & Modak, S. Management of desmoplastic small round cell tumor. Semin. Pediatr. Surg. 25, 299–304 (2016).
Lee, J. C. et al. Clinicopathologic and molecular features of intracranial desmoplastic small round cell tumors. Brain Pathol. 30, 213–225 (2019).
Casali, P. G. et al. Bone sarcomas: ESMO-PaedCan-EURACAN clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 29, iv79–iv95 (2018).
Casali, P. G. et al. Soft tissue and visceral sarcomas: ESMO-EURACAN clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 29, iv51–iv67 (2018).
Backer, A. et al. Desmoplastic small round cell tumour of unknown primary origin with lymph node and lung metastases: histological, cytological, ultrastructural, cytogenetic and molecular findings. Virchows Arch. 432, 135–141 (1998).
Ray-Coquard, I. et al. Sarcoma: concordance between initial diagnosis and centralized expert review in a population-based study within three European regions. Ann. Oncol. 23, 2442–2449 (2012).
Gronchi, A. et al. Soft tissue and visceral sarcomas: ESMO-EURACAN-GENTURIS clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 32, 1348–1365 (2021).
Sirisena, U. D. N., Rajakulasingam, R. & Saifuddin, A. Imaging of bone and soft tissue BCOR-rearranged sarcoma. Skelet. Radiol. 50, 1291–1301 (2021).
Morani, A. C. et al. Desmoplastic small round cell tumor: imaging pattern of disease at presentation. AJR Am. J. Roentgenol. 212, W45–W54 (2019).
Harrison, D. J., Parisi, M. T. & Shulkin, B. L. The role of 18F-FDG-PET/CT in pediatric sarcoma. Semin. Nucl. Med. 47, 229–241 (2017).
Wei, S. & Siegal, G. P. Small round cell tumors of soft tissue and bone. Arch. Pathol. Lab. Med. 146, 47–59 (2022).
Kallen, M. E. & Hornick, J. L. From the ashes of ‘Ewing-like’ sarcoma: a contemporary update of the classification, immunohistochemistry, and molecular genetics of round cell sarcomas. Semin. Diagn. Pathol. 39, 29–37 (2022).
Yoshida, A. et al. CIC break-apart fluorescence in-situ hybridization misses a subset of CIC-DUX4 sarcomas: a clinicopathological and molecular study. Histopathology 71, 461–469 (2017).
Ong, S. L. M. et al. Expanding the spectrum of EWSR1-NFATC2-rearranged benign tumors: a common genomic abnormality in vascular malformation/hemangioma and simple bone cyst. Am. J. Surg. Pathol. 45, 1669–1681 (2021).
Yoshida, K.-I. et al. NKX3-1 is a useful immunohistochemical marker of EWSR1-NFATC2 sarcoma and mesenchymal chondrosarcoma. Am. J. Surg. Pathol. 44, 719–728 (2020).
Hayes-Jordan, A., Green, H., Fitzgerald, N., Xiao, L. & Anderson, P. Novel treatment for desmoplastic small round cell tumor: hyperthermic intraperitoneal perfusion. J. Pediatr. Surg. 45, 1000–1006 (2010).
Strauss, S. J. et al. Bone sarcomas: ESMO-EURACAN-GENTURIS-ERN PaedCan clinical practice guideline for diagnosis, treatment and follow-up. Ann. Oncol. 32, 1520–1536 (2021).
Blay, J.-Y. et al. Surgery in reference centers improves survival of sarcoma patients: a nationwide study. Ann. Oncol. 30, 1143–1153 (2019).
Blay, J.-Y. et al. Improved survival using specialized multidisciplinary board in sarcoma patients. Ann. Oncol. 28, 2852–2859 (2017).
Davis, J. L. & Rudzinski, E. R. Small round blue cell sarcoma other than Ewing sarcoma: what should an oncologist know? Curr. Treat. Options Oncol. 21, 90 (2020).
Connolly, E. A. et al. Systemic treatments and outcomes in CIC-rearranged sarcoma: a national multi-centre clinicopathological series and literature review. Cancer Med. https://doi.org/10.1002/cam4.4580 (2022).
Mehdi, B. et al. Patterns of care and outcomes of 64 CIC-rearranged sarcoma: a retrospective multicentre case-series within the French Sarcoma Group (FSG). Ann. Oncol. 32, S1111–S1128 (2021).
Bexelius, T. S., Wasti, A. & Chisholm, J. C. Mini-review on targeted treatment of desmoplastic small round cell tumor. Front. Oncol. 10, 518 (2020).
Gerrand, C. et al. Seeking international consensus on approaches to primary tumour treatment in Ewing sarcoma. Clin. Sarcoma Res. 10, 21 (2020).
Ferrari, A. et al. Soft tissue sarcomas of childhood and adolescence: the prognostic role of tumor size in relation to patient body size. J. Clin. Oncol. 27, 371–376 (2009).
Hayes-Jordan, A. A. et al. Desmoplastic small round cell tumor treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: results of a phase 2 trial. Ann. Surg. Oncol. 25, 872–877 (2018).
Hayes-Jordan, A. et al. Complete cytoreduction and HIPEC improves survival in desmoplastic small round cell tumor. Ann. Surg. Oncol. 21, 220–224 (2014).
Mello, C. A. et al. Desmoplastic small round cell tumor: a review of main molecular abnormalities and emerging therapy. Cancers 13, 498 (2021).
Hendricks, A., Boerner, K., Germer, C.-T. & Wiegering, A. Desmoplastic small round cell tumors: a review with focus on clinical management and therapeutic options. Cancer Treat. Rev. 93, 102140 (2021).
Waqar, S. H. B., Ali, H., Sheikh, T. & Hamouda, D. M. Desmoplastic small round cell tumor: analysis of Surveillance, Epidemiology, and End Results (SEER) database 1975 to 2018 [abstract]. J. Clin. Oncol. 40 (Suppl. 16), e23540 (2022).
Dirksen, U. et al. Efficacy of add-on treosulfan and melphalan high-dose therapy in patients with high-risk metastatic Ewing sarcoma: report from the International Ewing 2008R3 trial [abstract]. J. Clin. Oncol. 38 (Suppl. 15), 11501 (2020).
Whelan, J. et al. High-dose chemotherapy and blood autologous stem-cell rescue compared with standard chemotherapy in localized high-risk Ewing sarcoma: results of Euro-E.W.I.N.G.99 and Ewing-2008. J. Clin. Oncol. https://doi.org/10.1200/JCO.2018.78.2516 (2018).
Koch, R. et al. High-dose treosulfan and melphalan as consolidation therapy versus standard therapy for high-risk (metastatic) Ewing sarcoma. J. Clin. Oncol. https://doi.org/10.1200/JCO.21.01942 (2022).
Scheer, M. et al. Desmoplastic small round cell tumors: multimodality treatment and new risk factors. Cancer Med. 8, 527–542 (2019).
Dancsok, A. R. et al. Expression of lymphocyte immunoregulatory biomarkers in bone and soft-tissue sarcomas. Mod. Pathol. 32, 1772–1785 (2019).
Blay, J.-Y. et al. High clinical benefit rates of single agent pembrolizumab in selected rare sarcoma histotypes: first results of the AcSé pembrolizumab study [abstract 1619O]. Ann. Oncol. 31 (Suppl. 4), S972 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03802071 (2022).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03317457 (2021).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03711279 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04551430 (2022).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03798106 (2021).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03277924 (2021).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04172805 (2021).
Weiner, L. M., Murray, J. C. & Shuptrine, C. W. Antibody-based immunotherapy of cancer. Cell 148, 1081–1084 (2012).
D’Angelo, S. P. et al. Antitumor activity associated with prolonged persistence of adoptively transferred NY-ESO-1 c259T cells in synovial sarcoma. Cancer Discov. 8, 944–957 (2018).
Endo, M. et al. NY-ESO-1 (CTAG1B) expression in mesenchymal tumors. Mod. Pathol. 28, 587–595 (2015).
Ahmed, N. et al. Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J. Clin. Oncol. 33, 1688–1696 (2015).
Hirabayashi, K. et al. Feasibility and immune response of WT1 peptide vaccination in combination with OK-432 for paediatric solid tumors. Anticancer. Res. 38, 2227–2234 (2018).
Tan, L.-C. et al. BCOR-CCNB3 rearranged sarcoma arising in neck misdiagnosed as thyroid cancer: a case report. Oral. Oncol. 120, 105290 (2021).
Donahue, J. E. et al. Primary spinal epidural CIC-DUX4 undifferentiated sarcoma in a child. Pediatr. Dev. Pathol. 21, 411–417 (2018).
Yang, S. et al. CIC-NUTM1 sarcomas affecting the spine: a subset of CIC-rearranged sarcomas commonly present in the axial skeleton. Arch. Pathol. Lab. Med. https://doi.org/10.5858/arpa.2021-0153-OA (2021).
Kushner, B. H. et al. Survival from locally invasive or widespread neuroblastoma without cytotoxic therapy. J. Clin. Oncol. 14, 373–381 (1996).
Ginsberg, J. P. et al. Long-term survivors of childhood ewing sarcoma: report from the Childhood Cancer Survivor Study. J. Natl Cancer Inst. 102, 1272–1283 (2010).
Hayes-Jordan, A., Green, H., Ludwig, J. & Anderson, P. Toxicity of hyperthermic intraperitoneal chemotherapy (HIPEC) in pediatric patients with sarcomatosis/carcinomatosis: early experience and phase 1 results. Pediatr. Blood Cancer 59, 395–397 (2012).
Paulussen, M. et al. Second malignancies after Ewing tumor treatment in 690 patients from a cooperative German/Austrian/Dutch study. Ann. Oncol. 12, 1619–1630 (2001).
Longhi, A. et al. Late effects of chemotherapy and radiotherapy in osteosarcoma and Ewing sarcoma patients: the Italian Sarcoma Group Experience (1983–2006). Cancer 118, 5050–5059 (2012).
Bent, M. A., Padilla, B. E., Goldsby, R. E. & DuBois, S. G. Clinical characteristics and outcomes of pediatric patients with desmoplastic small round cell tumor. Rare Tumors 8, 6145 (2016).
Marina, N. M. et al. Longitudinal follow-up of adult survivors of Ewing sarcoma: a report from the Childhood Cancer Survivor Study. Cancer 123, 2551–2560 (2017).
Ranft, A. et al. Quality of survivorship in a rare disease: clinicofunctional outcome and physical activity in an observational cohort study of 618 long-term survivors of Ewing sarcoma. J. Clin. Oncol. 35, 1704–1712 (2017).
Oyama, R. et al. Generation of novel patient-derived CIC-DUX4 sarcoma xenografts and cell lines. Sci. Rep. 7, 4712 (2017).
Lin, Y. K., Wu, W., Ponce, R. K., Kim, J. W. & Okimoto, R. A. Negative MAPK-ERK regulation sustains CIC-DUX4 oncoprotein expression in undifferentiated sarcoma. Proc. Natl Acad. Sci. USA 117, 20776–20784 (2020).
Uboldi, S. et al. Mechanism of action of trabectedin in desmoplastic small round cell tumor cells. BMC Cancer 17, 107 (2017).
Tirado, O. M., Mateo-Lozano, S. & Notario, V. Rapamycin induces apoptosis of JN-DSRCT-1 cells by increasing the Bax:Bcl-xL ratio through concurrent mechanisms dependent and independent of its mTOR inhibitory activity. Oncogene 24, 3348–3357 (2005).
van Erp, A. E. M. et al. Olaparib and temozolomide in desmoplastic small round cell tumors: a promising combination in vitro and in vivo. J. Cancer Res. Clin. Oncol. 146, 1659–1670 (2020).
Lowery, C. D. et al. Broad spectrum activity of the checkpoint kinase 1 inhibitor prexasertib as a single agent or chemopotentiator across a range of preclinical pediatric tumor models. Clin. Cancer Res. 25, 2278–2289 (2019).
Hayes-Jordan, A. A. et al. Efficacy of ONC201 in desmoplastic small round cell tumor. Neoplasia 20, 524–532 (2018).
Lamhamedi-Cherradi, S.-E. et al. The androgen receptor is a therapeutic target in desmoplastic small round cell sarcoma. Nat. Commun. 13, 3057 (2022). This paper describes a novel approach of repurposing androgen receptor-targeting drugs for the treatment of DSRCT.
Lowery, C. D. et al. Anti-VEGFR2 therapy delays growth of preclinical pediatric tumor models and enhances anti-tumor activity of chemotherapy. Oncotarget 10, 5523–5533 (2019).
Ogura, K. et al. Therapeutic potential of NTRK3 inhibition in desmoplastic small round cell tumor. Clin. Cancer Res. 27, 1184–1194 (2021).
Bleijs, M. et al. EWSR1-WT1 target genes and therapeutic options identified in a novel DSRCT in vitro model. Cancers 13, 6072 (2021).
Smith, R. S. et al. Novel patient-derived models of desmoplastic small round cell tumor confirm a targetable dependency on ERBB signaling. Dis. Model. Mech. 15, dmm047621 (2022).
Vanoli, F. et al. CRISPR-Cas9-guided oncogenic chromosomal translocations with conditional fusion protein expression in human mesenchymal cells. Proc. Natl Acad. Sci. USA 114, 3696–3701 (2017).
Spraggon, L. et al. Generation of conditional oncogenic chromosomal translocations using CRISPR-Cas9 genomic editing and homology-directed repair. J. Pathol. 242, 102–112 (2017).
Tanaka, M. & Nakamura, T. Modeling fusion gene-associated sarcoma: advantages for understanding sarcoma biology and pathology. Pathol. Int. 71, 643–654 (2021).
Watson, S. et al. CIC-DUX4 expression drives the development of small round cell sarcoma in transgenic zebrafish: a new model revealing a role for ETV4 in CIC-mediated sarcomagenesis. Preprint at bioRxiv https://doi.org/10.1101/517722 (2019).
Ignatiadis, M., Sledge, G. W. & Jeffrey, S. S. Liquid biopsy enters the clinic – implementation issues and future challenges. Nat. Rev. Clin. Oncol. 18, 297–312 (2021).
Shukla, N. N. et al. Plasma DNA-based molecular diagnosis, prognostication, and monitoring of patients with EWSR1 fusion-positive sarcomas. JCO Precis. Oncol. 2017, PO.16.00028 (2017).
Colletti, M. et al. Expression profiles of exosomal miRNAs isolated from plasma of patients with desmoplastic small round cell tumor. Epigenomics 11, 489–500 (2019).
Ferreira, E. N. et al. A genomic case study of desmoplastic small round cell tumor: comprehensive analysis reveals insights into potential therapeutic targets and development of a monitoring tool for a rare and aggressive disease. Hum. Genomics 10, 36 (2016).
Shulman, D. S. et al. Detection of circulating tumour DNA is associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Children’s Oncology Group. Br. J. Cancer 119, 615–621 (2018).
Specht, K. et al. Distinct transcriptional signature and immunoprofile of CIC-DUX4 fusion-positive round cell tumors compared to EWSR1-rearranged Ewing sarcomas: further evidence toward distinct pathologic entities. Genes Chromosomes Cancer 53, 622–633 (2014).
Ponce, R. K. M., Thomas, N. J., Bui, N. Q., Kondo, T. & Okimoto, R. A. WEE1 kinase is a therapeutic vulnerability in CIC-DUX4 undifferentiated sarcoma. JCI Insight 7, e152293 (2022).
Nishio, J. et al. Establishment and characterization of a novel human desmoplastic small round cell tumor cell line, JN-DSRCT-1. Lab. Invest. 82, 1175–1182 (2002).
Emanuela P. et al. Graceful project: a global collaboration on CIC-DUX4, BCOR-CCNB3, high grade undifferentiated round cell sarcoma (URCS). in Proceedings of the CTOS Annual Meeting vol. ID 3251212 (ed. Kawai, A.) (CTOS, 2019).
Graham, C., Chilton-MacNeill, S., Zielenska, M. & Somers, G. R. The CIC-DUX4 fusion transcript is present in a subgroup of pediatric primitive round cell sarcomas. Hum. Pathol. 43, 180–189 (2012).
Bode-Lesniewska, B., Fritz, C., Exner, G. U., Wagner, U. & Fuchs, B. EWSR1-NFATC2 and FUS-NFATC2 gene fusion-associated mesenchymal tumors: clinicopathologic correlation and literature review. Sarcoma 2019, 9386390 (2019).
Quelle, D. E., Zindy, F., Ashmun, R. A. & Sherr, C. J. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 83, 993–1000 (1995).
Glendening, J. M. et al. Homozygous loss of the p15INK4B gene (and not the p16INK4 gene) during tumor progression in a sporadic melanoma patient. Cancer Res. 55, 5531–5535 (1995).
Shang, C., Guo, Y., Hong, Y. & Xue, Y.-X. Long non-coding RNA TUSC7, a target of miR-23b, plays tumor-suppressing roles in human gliomas. Front. Cell Neurosci. 10, 235 (2016).
Cichowski, K. & Jacks, T. NF1 tumor suppressor gene function: narrowing the GAP. Cell 104, 593–604 (2001).
Ron, D. et al. Fibroblast growth factor receptor 4 is a high affinity receptor for both acidic and basic fibroblast growth factor but not for keratinocyte growth factor. J. Biol. Chem. 268, 5388–5394 (1993).
Fyodorov, D. V., Zhou, B.-R., Skoultchi, A. I. & Bai, Y. Emerging roles of linker histones in regulating chromatin structure and function. Nat. Rev. Mol. Cell Biol. 19, 192–206 (2018).
Fondevila, F., Méndez-Blanco, C., Fernández-Palanca, P., González-Gallego, J. & Mauriz, J. L. Anti-tumoral activity of single and combined regorafenib treatments in preclinical models of liver and gastrointestinal cancers. Exp. Mol. Med. 51, 1–15 (2019).
Menegaz, B. A. et al. Clinical activity of pazopanib in patients with advanced desmoplastic small round cell tumor. Oncologist 23, 360–366 (2018).
Bukowski, R. M., Yasothan, U. & Kirkpatrick, P. Pazopanib. Nat. Rev. Drug Discov. 9, 17–18 (2010).
Miyamoto, S. et al. Drug review: pazopanib. Jpn. J. Clin. Oncol. 48, 503–513 (2018).
Frezza, A. M. et al. Pazopanib in advanced desmoplastic small round cell tumours: a multi-institutional experience. Clin. Sarcoma Res. 4, 7 (2014).
Jayakrishnan, T. et al. Desmoplastic small round-cell tumor: retrospective review of institutional data and literature review. Anticancer. Res. 41, 3859–3866 (2021).
Ferrari, A. et al. Trabectedin-irinotecan, a potentially promising combination in relapsed desmoplastic small round cell tumor: report of two cases. J. Chemother. https://doi.org/10.1080/1120009X.2022.2067706 (2022).
Verret, B. et al. Trabectedin in advanced desmoplastic round cell tumors: a retrospective single-center series. Anticancer. Drugs 28, 116–119 (2017).
Frezza, A. M., Whelan, J. S. & Dileo, P. Trabectedin for desmoplastic small round cell tumours: a possible treatment option? Clin. Sarcoma Res. 4, 3 (2014).
Brunetti, A. E. et al. Third-line trabectedin for a metastatic desmoplastic small round cell tumour treated with multimodal therapy. Anticancer. Res. 34, 3683–3688 (2014).
Chao, J. et al. Phase II clinical trial of imatinib mesylate in therapy of KIT and/or PDGFRα-expressing Ewing sarcoma family of tumors and desmoplastic small round cell tumors. Anticancer. Res. 30, 547–552 (2010).
O’Brien, S. G. et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med. 348, 994–1004 (2003).
Vennepureddy, A., Singh, P., Rastogi, R., Atallah, J. P. & Terjanian, T. Evolution of ramucirumab in the treatment of cancer – a review of literature. J. Oncol. Pharm. Pract. 23, 525–539 (2017).
Bailey, K. et al. Targeted radioimmunotherapy for embryonal tumor with multilayered rosettes [abstract THER-24]. Neuro Oncol. 21, ii118–ii119 (2019).
Slotkin, E. K. et al. A phase I/II study of prexasertib in combination with irinotecan in patients with relapsed/refractory desmoplastic small round cell tumor and rhabdomyosarcoma [abstract]. J. Clin. Oncol. 40 (Suppl. 16), 11503 (2022).
Wedekind, M. F. et al. Immune profiles of desmoplastic small round cell tumor and synovial sarcoma suggest different immunotherapeutic susceptibility upfront compared to relapse specimens. Pediatr. Blood Cancer 65, e27313 (2018).
Chew, G.-L. et al. DUX4 suppresses MHC class I to promote cancer immune evasion and resistance to checkpoint blockade. Dev. Cell 50, 658–671.e7 (2019).
McCaffrey, P. G. et al. Isolation of the cyclosporin-sensitive T cell transcription factor NFATp. Science 262, 750–754 (1993).
Tan, Q. et al. Loss of Capicua alters early T cell development and predisposes mice to T cell lymphoblastic leukemia/lymphoma. Proc. Natl Acad. Sci. USA 115, E1511–E1519 (2018).
Davis, K. L. et al. Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, phase 1–2 trial. Lancet Oncol. 21, 541–550 (2020).
T.G.P.G. was supported by the Matthias-Lackas Foundation, the Dr. Leopold and Carmen Ellinger Foundation, the German Cancer Aid (DKH-70114278 and DKH-70114111), the Gert und Susanna Mayer Foundation, the Boehringer-Ingelheim Foundation, the Federal Ministry of Education and Research (BMBF: SMART-CARE; HEROES-AYA), the Deutsche Forschungsgemeinschaft (DFG-458891500), the SMARCB1 association, and the Barbara und Wilfried Mohr Foundation. F.C.-A. was supported by grants from the Barbara & Hubertus Trettner Foundation, and the Dr. Rolf M. Schwiete Foundation, and the German Cancer Aid. The authors express their apologies to all authors whose valuable work could not be cited owing to space constraints.
The authors declare no competing interests.
Peer review information
Nature Reviews Disease Primers thanks K. Thway, P. Rutkowski and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Cidre-Aranaz, F., Watson, S., Amatruda, J.F. et al. Small round cell sarcomas. Nat Rev Dis Primers 8, 66 (2022). https://doi.org/10.1038/s41572-022-00393-3